ГЕНЕТИЧЕСКИ МОДИФИЦИРОВАННЫЕ, НЕ ПРИНАДЛЕЖАЩИЕ К ЧЕЛОВЕЧЕСКОМУ РОДУ ЖИВОТНЫЕ И СПОСОБ ИХ ИСПОЛЬЗОВАНИЯ

... 1. Генетически модифицированное не принадлежащее к человеческому роду животное, содержащее в своем геноме нуклеиновую кислоту, кодирующую человеческий M-CSF, нуклеиновую кислоту, кодирующую человеческий IL-3, нуклеиновую кислоту, кодирующую человеческий GM-CSF, нуклеиновую кислоту, кодирующую человеческий SIRPA и нуклеиновую кислоту, кодирующую человеческий ТРО, при этом каждая из нуклеиновых кислот, кодирующих человеческий M-CSF, человеческий IL-3, человеческий GM-CSF, человеческий SIRPA и человеческий ТРО является функционально связанной с промотором, и при этом животное экспрессирует полипептид M-CSF человека, полипептид IL-3 человека, полипептид GM-CSF человека, полипептид SIRPA человека и полипептид ТРО человека.2. Генетически модифицированное не принадлежащее к человеческому роду животное по п. 1, согласно которому животное является имунодефицитным.3. Генетически модифицированное, иммунодефицитное, не принадлежащее к человеческому роду животное по п. 2, отличающееся тем, что у животного ...

ПРИМЕНЕНИЕ РАЗМНОЖЕННЫХ ПОПУЛЯЦИЙ ГЕМАТОПОЭТИЧЕСКИХ СТВОЛОВЫХ КЛЕТОК/КЛЕТОК-ПРЕДШЕСТВЕННИКОВ

РОССИЙСКАЯ ФЕДЕРАЦИЯ (19) RU (11) (13) 2018 124 303 A (51) МПК C12N 5/02 (2006.01) ФЕДЕРАЛЬНАЯ СЛУЖБА ПО ИНТЕЛЛЕКТУАЛЬНОЙ СОБСТВЕННОСТИ (12) ЗАЯВКА НА ИЗОБРЕТЕНИЕ (21)(22) Заявка: 2018124303, 05.12.2016 (71) Заявитель(и): ФРЕД ХАТЧИНСОН КЭНСЕР РИСЕРЧ СЕНТЕР (US) Приоритет(ы): (30) Конвенционный приоритет: 04.12.2015 US 62/263,470; 04.12.2015 US 62/263,573 (72) Автор(ы): ДЕЛЕЙНИ, Коллин (US) (85) Дата начала рассмотрения заявки PCT на национальной фазе: 04.07.2018 US 2016/064908 (05.12.2016) (87) Публикация заявки PCT: R U Адрес для переписки: 129090, Москва, ул. Б.Спасская, 25, строение 3, ООО "Юридическая фирма Городисский и Партнеры" (54) ПРИМЕНЕНИЕ РАЗМНОЖЕННЫХ ПОПУЛЯЦИЙ ГЕМАТОПОЭТИЧЕСКИХ СТВОЛОВЫХ КЛЕТОК/КЛЕТОК-ПРЕДШЕСТВЕННИКОВ (57) Формула изобретения 1. Применение обогащенного CD34+ и размноженного продукта пуповинной крови для индуцирования иммуннологической толерантности у реципиента трансплантата, где продукт пуповинной крови не соответствует по HLA реципиенту трансплантата, и трансплантат является совместимым по HLA или не полностью совместимым по HLA с реципиентом трансплантата. 2. Способ индуцирования иммуннологической толерантности у реципиента трансплантата, включающий введение терапевтически эффективного количества обогащенного CD34+ и размноженного продукта пуповинной крови, таким образом, индуцирование иммуннологической толерантности у реципиента трансплантата, где продукт пуповинной крови не соответствует по HLA реципиенту трансплантата, и трансплантат является совместимым по HLA или не полностью совместимым по HLA с реципиентом трансплантата. 3. Применение по п.1 или способ по п.2, где трансплантат является HLA-совместимым по 6/6 антигенам HLA или не полностью совместимым по HLA по 1/6 или 2/6 антигенам HLA с реципиентом трансплантата. 4. Применение по п.1 или способ по п.2, где продукт пуповинной крови наращивали в культуре, содержащей Delta1; или Стр.: 1 A 2 0 1 8 1 2 4 3 0 3 A WO 2017/096347 (08.06.2017) 2 0 1 8 1 2 4 3 0 3 (86) Заявка PCT: R ...

МЫШИ, ЭКСПРЕССИРУЮЩИЕ ЛЕГКУЮ ЦЕПЬ С ВАРИАБЕЛЬНОЙ ОБЛАСТЬЮ λ ЧЕЛОВЕКА И КОНСТАНТНОЙ ОБЛАСТЬЮ МЫШИ

ЖИВОТНЫЕ, ОТЛИЧНЫЕ ОТ ЧЕЛОВЕКА, С НАРУШЕНИЕМ В ЛОКУСЕ C9ORF72

ОТЛИЧНЫЕ ОТ ЧЕЛОВЕКА ЖИВОТНЫЕ С ГУМАНИЗИРОВАННЫМ ГЕНОМ СИГНАЛЬНОГО РЕГУЛЯТОРНОГО БЕЛКА

BAFF, DESSEN INHIBITOREN UND DESSEN VERWENDUNG ZUR MODULIERUNG DER B-ZELL-ANTWORT

Polypeptide

Ligands for flt3 receptors

PROCEDURE FOR THE MODULATION OF HEMATOPOIESIS AND VASCULAR GROWTH

USE OF AN ANTIBODY APPROXIMATELY WATER-SOLUBLY BAFF FOR CANCER TREATMENT

PROCEDURE FOR THE MODULATION OF THE IMMUNE REACTION IN A INFEKTIERTEN MAMMAL OF MEANS OF TRANSMUKOSALES ENTERING MODULATION MEANS

High activity regulatory elements

Provided herein are compositions and methods for driving high expression of a transgene. Compositions and methods for driving high expression of a transgene comprising one or more human-derived regulatory elements, which, when operably linked to a transgene, can result in high expression of the transgene in one or more cell types or tissues.

Targeting of SALL4 for the treatment and diagnosis of proliferative disorders associated with myelodysplastic syndrome (MDS)

T cell regulation

TRANSGENIC ANIMALS BEARING HUMAN IgLamda LIGHT CHAIN GENES

Method for generating immortal dendritic cell lines

Genetically modified non-human animals and methods of use thereof

The invention relates generally to genetically modified non-human animals expressing human polypeptides and their methods of use.

MrgprX2/MrgprB2 expressing cell based assay to detect pseudo-allergic drug reactions and to identify blockers to prevent the adverse reactions

The present invention relates to cells and methods for detecting compounds that induce a pseudo-allergic-type reaction and methods for reducing the severity of a pseudo-allergic-type reaction.

NON-HUMAN ANIMALS HAVING A HUMANIZED SIGNAL-REGULATORY PROTEIN GENE

Genetically modified non-human animals and methods and compositions for making and using the same are provided, wherein the genetic modification comprises a humanization of an endogenous signal-regulatory protein gene, in particular a humanization of a SIRPa gene. Genetically modified mice are described, including mice that express a human or humanized SIRPa protein from an endogenous SIRPa locus.

MEANS FOR THE IDENTIFICATION OF COMPOUNDS CAPABLE OF INHIBITING KARAP-TRANSDUCED SIGNALS

The present application relates to transgenic animals over-expressing KARAP, knock-in animals bearing non functional KARAP, and to method and kits for the identification of compounds capable of inhibiting a KARAP-transduced immune signal.

CLONING B AND T LYMPHOCYTES

This invention includes methods for producing non-human mammals expressing monoclonal or oligoclonal B or T lymphocytes, as well as embryonic and hematopoietic stem cells that differentiate into monoclonal or oligoclonal B or T cells, using cloning by nuclear transfer with a B or T cell of interest as the nuclear donor cell.

NON-HUMAN TRANSGENIC MAMMALS USED AS MODELS FOR HUMAN PATHOLOGIES ORIGINATING FROM STEM CELLS

The invention relates to non-human transgenic mammals which reproduce human pathologies originating from stem cells, e.g. chromosomal anomalies associated with chronic myeloid leukaemia, B-cell lineage acute lymphoblastic leukaemia, T-cell lineage acute lymphoblastic leukaemia, or the migration of hematopoietic or embryonic stem cells. The invention makes use of the expression of the genes involved in said pathology in human beings, employing a promoter which directs the expression of a transgene in cells Sca-1+. The aforementioned transgenic animals form a model which is used to study the above-mentioned diseases and to evaluate compounds for treating and/or preventing said diseases.

HUMAN ANTIBODY PRODUCING MOUSE AND METHOD FOR PRODUCING HUMAN ANTIBODY USING THE SAME

Disclosed is a human antibody producing mouse, which carries: (a) an unrearranged human antibody heavy chain gene locus, (b) an unrearranged human antibody .kappa. light chain gene locus and (c) an unrearranged human antibody .lambda. light chain gene locus, wherein at least one of (a), (b) and (c) is retained on one or more human derived chromosome fragments and at least one of (a), (b) and (c) is inserted into a mouse chromosome, and further wherein at least both alleles of endogenous heavy chains and both alleles of endogenous .kappa. light chains are inactivated, and the mouse expresses human antibody heavy chain, human antibody .kappa. light chain and human antibody .lambda. light chain in serum of the mouse. The mouse is useful in producing human antibodies.

METHODS AND COMPOSITIONS FOR MODULATION OF STEM CELL AGING

Methods are described for promoting or maintaining self-renewal of a stem cell expressing or expected to express p16INK4a by employing p16INK4a inhibitors. Methods are also described for increasing the amount of self-renewing stem cells in a non-infant subject, as well as for enhancing engraftment of a stem cell expressing p16INK4a. Additionally, methods are described for identifying p16INK4a inhibitors.

NON-HUMAN ANIMALS HAVING A HUMANIZED CLUSTER OF DIFFERENTIATION 47 GENE

Non-human animals, and methods and compositions for making and using the same, are provided, wherein said non-human animals comprise a humanization of an endogenous cluster of differentiation (CD) gene, in particular a humanization of a CD47 gene. Said non-human animals may be described, in some embodiments, as having a genetic modification to an endogenous CD47 gene so that said non-human animals express a CD47 polypeptide that includes a human portion and a non-human portion (e.g., a murine portion).

MICE EXPRESSING ALIGHT CHAIN WITH HUMAN LAMBDA VARIABLE AND MOUSE CONSTANT REGIONS

Genetically modified mice are provided that express human ? variable (hV?) sequences, including mice that express hV? sequences from an endogenous mouse ? light chain locus, mice that express hV? sequences from an endogenous mouse ? light chain locus, and mice that express hV? sequences from a transgene or an episome wherein the hV? sequence is linked to a mouse constant sequence. Mice are provided that are a source of somatically mutated human ? variable sequences useful for making antigen- binding proteins. Compositions and methods for making antigen-binding proteins that comprise human ? variable sequences, including human antibodies, are provided.

MODULATION OF BCL11A FOR TREATMENT OF HEMOGLOBINOPATHIES

The invention relates to methods and uses of modulating fetal hemoglobin expression (HbF) in a hematopoietic progenitor cells via inhibitors of BCL11A expression or activity, such as RNAi and antibodies.

LIGANDS FOR FLT3 RECEPTORS

Ligands for flt3 receptors capable of transducing self renewal signals to regulate the growth, proliferation or differentiation of progenitor cells and stem cells are disclosed. The invention is directed to flt3-L as an isolated protein, the DNA encoding the Flt3-L, host cells transfected with cDNAs encoding flt3-L, compositions comprising flt3-L , methods of improving gene transfer to a mammal using flt3-L, and methods of improving transplantations using flt3-L. Flt3-L finds use in treating patients with anemia, AIDS and various cancels.

METHODS OF TREATMENT AND/OR PREVENTION OF REACTION AGAINST TRANSPLANT HOST, AND/OR DIFFUSE ALVEOLAR HEMORRHAGE, AND/OR VENOOKKLYuZIONNOI DISEASE, ASSOCIATED WITH TRANSPLANT HEMOPOIETIC STEM CELLS

СПОСОБЫ СТИМУЛЯЦИИ И ИНГИБИРОВАНИЯ РОСТА В-КЛЕТОК, ПРОДУЦИРОВАНИЯ ИММУНОГЛОБУЛИНОВ И КОРРЕКЦИИ НАРУШЕНИЙ, СВЯЗАННЫХ С BAFF-ЛИГАНДОМ, У ЖИВОТНОГО

Данное изобретение связано со способами стимуляции и ингибирования роста В-клеток и со способами лечения или предупреждения нарушений, связанных с экспрессией BAFF-лиганда, с применением BAFF-лиганда и его активных фрагментов и антител, специфичных в отношении BAFF-лиганда.

BAFF, RELATED TO IT BLOCKING AGENTS AND THEIR USE IN STIMULATION AND INHIBITION OF B-CELLS AND IMMUNOGLOBULINS IN IMMUNE REACTIONS

Transgenic animal cell, useful for studying the human immune system and as a transplant cell, comprises a human transgene targeted to and interrupting the animal homologue implicated in antigenic recognition or T cell activity

L'invention se rapporte à une cellule animale, isolée, comprenant au moins un transgène comprenant au moins une séquence nucléotidique codant pour au moins un polypeptide humain impliqué dans la reconnaissance et/ ou dans l'activation antigénique par les cellules T, caractérisée en ce que ladite cellule, ou une descendante de ladite cellule, exprime au moins tout ou partie du ou desdits polypeptide (s) humain (s), et caractérisée en ce que le gène animal endogène homologue codant pour un polypeptide animal homologue audit polypeptide humain est invalide. L'invention porte également sur l'animal transgénique correspondant. La cellule et l'animal transgénique selon l'invention peuvent être mis en oeuvre dans un procédé de criblage de composés qui modulent une réaction immune chez l'homme. L'invention porte également sur l'utilisation de la cellule selon l'invention comme cellule rendue autologue ou tolérée par le système immunitaire.

CELLS AND ANIMAL TRANSGENIQUES Of STUDY OF the POLARIZATION Of the REPONSEIMMUNE

CELLS AND ANIMAL TRANSGENIQUES Of STUDY OF the POLARIZATION Of the REPONSEIMMUNE

CELLS AND ANIMAL TRANSGENIQUES Of STUDY OF the POLARIZATION Of the REPONSEIMMUNE

CELLS AND ANIMAL TRANSGENIQUES Of STUDY OF the POLARIZATION Of the REPONSEIMMUNE

CELLS AND ANIMAL TRANSGENIQUES Of STUDY OF the POLARIZATION Of the REPONSEIMMUNE

HYBRID LIGHT CHAIN MICE

TRANSGENIC IMMUNODEFICIENT MOUSE EXPRESSING HUMAN SIRPα

The present invention provides a transgenic mouse which comprises a deficiency for murine T lymphocytes, B lymphocytes and NK cells, a deficiency for murine MHC class I and MHC class II molecules, and a functional xenogenic SIRPα transgene. This mouse is useful for in vivo screening of various compounds, including immuno-therapeutic agents and vaccines. The said mouse is also useful for testing the in vivo metabolism of xenobiotic compounds.

USE OF EPHRINS AND RELATED MOLECULES TO REGULATE CELLULAR PROLIFERATION

Disclosed are nucleic acids, peptides, proteins, fusion proteins, antibodies, affibodies, and other reagents that disrupt interactions between ephrins and ephrin receptors. Specifically disclosed are reagents comprising soluble ephrins and soluble ephrin receptors. Also disclosed are methods of using these reagents for the increasing or decreasing cellular proliferation, for example, for alleviation, prevention, or treatment of one or more symptoms of a disease or disorder, including a disease or disorder of the gastrointestinal tract, reproductive tract, skin, or hematopoietic system.

TARGETING OF SALL4 FOR THE TREATMENT AND DIAGNOSIS OF PROLIFERATIVE DISORDERS ASSOCIATED WITH MYELODYSPLASTIC SYNDROME (MDS)

The present invention discloses nucleic acids, proteins, and antibodies for SALL4 (including isoforms SALL4A, SALL4B, and SALL4C), a zinc finger transcriptional factor. Further, methods are disclosed which demonstrate that constitutive expression of SALL4 increases leukemogenic potential in cells of model animal systems. Moreover, constitutive expression of select isoforms (e.g., SALL4B) in transgenic mice demonstrate that these animals develop myelodysplastic syndrome (MDS)-like signs and symptoms, including subsequent acute myeloid leukemia (AML), which is transplantable. The disclosure also provides methods for identifying and purifying embryonic stem cells, adult stem cells, cancer stem cells, including leukemia stem cells, methods for identifying substances which bind to and/or modulate SALL4, methods for diagnosing MDS in a subject, and methods of treating a subject presenting MDS.

GENETICALLY MODIFIED MICE AND ENGRAFTMENT

A mouse with a humanization of the mIL-3 gene and the mGM-CSF gene, a knockout of a mRAG gene, and a knockout of a mIl2rg subunit gene; and optionally a humanization of the TPO gene is described. A RAG/Il2rg KO/hTPO knock-in mouse is described. A mouse engrafted with human hematopoietic stem cells (HSCs) that maintains a human immune cell (HIC) population derived from the HSCs and that is infectable by a human pathogen, e.g., S. typhi or M. tuberculosis is described. A mouse that models a human pathogen infection that is poorly modeled in mice is described, e.g., a mouse that models a human mycobacterial infection, wherein the mouse develops one or more granulomas comprising human immune cells. A mouse that comprises a human hematopoietic malignancy that originates from an early human hematopoietic cells is described, e.g., a myeloid leukemia or a myeloproliferative neoplasia.

Universal donor cells

Genetically engineered cells are provided which can serve as universal donor cells in such applications as reconstruction of vascular linings or the administration of therapeutic agents. The cells include a coding region which provides protection against complement-based lysis, i.e., hyperacute rejection. In addition, the cell's natural genome is changed so that functional proteins encoded by either the class II or both the class I and the class II major histocompatibility complex genes do not appear on the cell's surface. In this way, attack by T-cells is avoided. Optionally, the cells can include a self-destruction mechanism so that they can be removed from the host when no longer needed.

Type iii allergic inflammation model animal

The present invention provides an experimental model animal which does not develop anaphylaxis, a type I allergy, can specifically induce Arthus reaction, a type III allergy, is not affected by type I allergy and evaluates type III allergy inflammation individually, and a method of screening a reaction accelerating or inhibitory substance in a type III allergy reaction through FcγRIII by using said experimental model animal. In order to eliminate FcγRIIB that demonstrates suppressive action to response through FrγRIII, a mouse wherein the deletion mutation of both molecules of Lyn and FcγRIIB are homozygotic (Lyn−IIB−) was generated by mating Lyn knockout mouse (Lyn−/−) and FcγRIIB knockout mouse (FcγRIIB−/−), and was used to measure and evaluate the deficiency of FcγRIII function in systemic passive anaphylaxis and the reduction of FcγRIII function in a bone marrow-derived mast cell, or the like.

Human CTLA-4 antibodies and their uses

The present invention provides novel human sequence antibodies against human CTLA-4 and methods of treating human diseases, infections and other conditions using these antibodies.

Mammalian gene modification method using electroporation

An object is to develop a technology enabling utilization, by only an extremely simple technique, of a technology which is widely applicable to mammals without requiring the utilization of an ES cell, and which involves modifying a certain gene by targeting a certain sequence on a genome (genome editing technology based on ZFN or the like). Provided is a technology for efficiently modifying an arbitrary target gene of a mammal, by immersing a pronuclear stage mammalian zygote with an intact zona pellucida into a solution containing a pair of molecules of mRNA having a certain sequence, and performing electroporation treatment through application of multiple square-wave pulses in three steps with the total electric energy of a first electric pulse adjusted within a predetermined range.

Methods for inhibiting hematopoiesis with a hedgehog antagonist

This application pertains to methods and compositions that modulate proliferation and/or differentiation of undifferentiated mesodermally-derived cells so as to have an effect on at least one of vascular growth and hematopoiesis.

Human artificial chromosome containting human antibody lambda light chain and non-human animal containting the human artificial chromosome capable of genetic transmission

The present invention relates to a human artificial chromosome which is genetically transmissible to the next generation with high efficiency and the method for using the same. More specifically, the present invention relates to: a human artificial chromosome in which an about 3.5 Mb to about 1 Mb region containing an antibody λ light chain gene derived from human chromosome 22 is bound to a chromosome fragment which is transmissible to a progeny through a germ line of a non-human animal, said chromosome fragment is derived from another human chromosome; a non-human animal carrying the human artificial chromosome and an offspring thereof; a method for producing the non-human animal; a method for producing a human antibody using the non-human animal or an offspring thereof; and a human antibody-producing mouse carrying the human artificial chromosome.

T CELL REGULATION

Regulatory T cells (Treg) limit autoimmunity but can also attenuate the magnitude of anti-pathogen and anti-tumor immunity. Understanding the mechanism of Treg function and therapeutic manipulation of Treg in vivo requires identification of Treg selective receptors. A comparative analysis of gene expression arrays from antigen specific CD4+ T cells differentiating to either an effector/memory or a regulatory phenotype revealed Treg selective expression of LAG-3 (CD223), a CD4-related molecule that binds MHC class II. LAG-3 expression on CD4+ T cells correlates with the cells' in vitro suppressor activity, and ectopic expression of LAG-3 on CD4 T cells confers suppressor activity on the T cells. Antibodies to LAG-3 inhibit suppression both in vitro and in vivo. LAG-3 marks regulatory T cell populations and contributes to their suppressor activity.

ADULT T CELL LEUKEMIA MODEL ANIMAL

Methods for producing human lymphocytes and human monoclonal antibodies, and human monoclonal antibodies produced thereby

FORMATION OF HETEROANTIBODY

PROBLEM TO BE SOLVED: To provide a new DNA that has a homology to the gene locus of the endogenous immunoglobulin, inactivates this gene locus by the homologous recombination between the DNA sequence and this gene locus, and is useful for preparation of' cells producing human antibody by responding to the immunogen. SOLUTION: This is a DNA for inactivating the gene locus for endogenous immunoglobulin, includes a DNA sequence having partial homology to the gene locus of this endogenous immunoglobulin. This DNA sequence is used to effect the homologous recombination with the gene focus of the endogenous immunoglobulin whereby a lesion is at least partially introduced into the gene locus of' the endogenous immunoglobulin to prepare a novel DNA inactivating the gene locus. This novel DNA responds to immunogen and is useful for preparation of mammalian cells of non-primates producing human antibody car its analogue. This DNA contains the variable region, the ligation region and the stationary ...

ОТЛИЧНЫЕ ОТ ЧЕЛОВЕКА ЖИВОТНЫЕ С ГУМАНИЗИРОВАННЫМ ГЕНОМ СИГНАЛЬНОГО РЕГУЛЯТОРНОГО БЕЛКА

Изобретение относится к области биохимии, в частности к мыши для экспрессии гуманизированного белка SIRPα, содержащей замещение экзонов 2, 3 и 4 гена SIRPα мыши в эндогенном локусе SIRPα мыши на экзоны 2, 3 и 4 гена SIRPα человека с образованием гуманизированного гена SIRPα, а также к клетке и ткани вышеуказанной мыши. Также раскрыт способ получения вышеуказанной мыши. Изобретение также относится к способу трансплантации человеческих гематопоэтических клеток мыши, способу фагоцитоза меченого субстрата, способу изменения фагоцитоза, а также к способу оценки терапевтической эффективности потенциального лекарственного средства с использованием вышеуказанной мыши или ее клетки. Изобретение эффективно в использовании для анализов приживления трансплантата, активации фагоцитоза и сигнальной трансдукции. 8 н. и 9 з.п. ф-лы, 8 ил., 5 табл., 4 пр.

НАПРАВЛЕННАЯ МОДИФИКАЦИЯ ГЕНОМА КРЫСЫ

FIELD: biochemistry.SUBSTANCE: invention relates to the field of biochemistry, in particular, to a method for targeted modification of a genomic locus of interest in one or more pluripotent rat cells, comprising introducing into pluripotent rat cells a large targeting vector (LTVEC) comprising an insert nucleic acid, and identifying a genetically modified pluripotent rat cell comprising the targeted genetic modification in the genomic locus of interest, and also to a method of creating a humanised rat using said modification method. Also disclosed is a method for targeted modification of a genomic locus of interest in a population of pluripotent rat cells to obtain a genetically modified rat, including providing a population of pluripotent rat cells, obtaining a clone of a pluripotent rat cell, introducing said clone of pluripotent rat cells into a rat host embryo, and incubating said rat host embryo.EFFECT: invention makes it possible to efficiently obtain a genetically modified rat.92 cl, 33 dwg, 23 tbl, 5 ex РОССИЙСКАЯ ФЕДЕРАЦИЯ (19) RU (11) (13) 2 676 708 C2 (51) МПК A01K 67/027 (2006.01) C12N 15/85 (2006.01) ФЕДЕРАЛЬНАЯ СЛУЖБА ПО ИНТЕЛЛЕКТУАЛЬНОЙ СОБСТВЕННОСТИ (12) ОПИСАНИЕ ИЗОБРЕТЕНИЯ К ПАТЕНТУ (52) СПК A01K 67/0276 (2006.01); A01K 67/0278 (2006.01); C12N 15/8509 (2006.01); C12N 15/907 (2006.01) (21)(22) Заявка: 2015148637, 16.04.2014 (24) Дата начала отсчета срока действия патента: Дата регистрации: 10.01.2019 (73) Патентообладатель(и): РЕГЕНЕРОН ФАРМАСЬЮТИКАЛС, ИНК. (US) 16.04.2013 US 61/812,319; 11.12.2013 US 61/914,768 (43) Дата публикации заявки: 22.05.2017 Бюл. № 15 (56) Список документов, цитированных в отчете о поиске: US2004018626 A1, 29.01.2004. US2012272349 A1, 25.10.2012. WO2012129198 A1, 27.09.2012. RU 2290441 C2, 27.12.2006. (45) Опубликовано: 10.01.2019 Бюл. № 1 C 2 C 2 (85) Дата начала рассмотрения заявки PCT на национальной фазе: 16.11.2015 (86) Заявка PCT: US 2014/034412 (16.04.2014) 2 6 7 6 7 0 8 (87) Публикация заявки PCT: R U 2 6 7 6 7 0 8 ...

Patent RU2016110462A3

`7ВУ’” 2016110462`” АЗ Дата публикации: 30.03.2018 Форма № 18 ИЗИМ-2011 Федеральная служба по интеллектуальной собственности Федеральное государственное бюджетное учреждение ж 5 «Федеральный институт промышленной собственности» (ФИПС) ОТЧЕТ О ПОИСКЕ 1. . ИДЕНТИФИКАЦИЯ ЗАЯВКИ Регистрационный номер Дата подачи 2016110462/10(016486) 23.09.2014 РСТД52014/056910 23.09.2014 Приоритет установлен по дате: [ ] подачи заявки [ ] поступления дополнительных материалов от к ранее поданной заявке № [ ] приоритета по первоначальной заявке № из которой данная заявка выделена [ ] подачи первоначальной заявки № из которой данная заявка выделена [ ] подачи ранее поданной заявки № [Х] подачи первой(ых) заявки(ок) в государстве-участнике Парижской конвенции (31) Номер первой(ых) заявки(ок) (32) Дата подачи первой(ых) заявки(ок) (33) Код страны 1. 61/881,261 23.09.2013 05 Название изобретения (полезной модели): [Х] - как заявлено; [ ] - уточненное (см. Примечания) ОТЛИЧНЫЕ ОТ ЧЕЛОВЕКА ЖИВОТНЫЕ С ГУМАНИЗИРОВАННЫМ ГЕНОМ СИГНАЛЬНОГО РЕГУЛЯТОРНОГО БЕЛКА Заявитель: РЕГЕНЕРОН ФАРМАСЬЮТИКАЛС, ИНК., 05 2. ЕДИНСТВО ИЗОБРЕТЕНИЯ [Х] соблюдено [ ] не соблюдено. Пояснения: см. Примечания 3. ФОРМУЛА ИЗОБРЕТЕНИЯ: [Х] приняты во внимание все пункты (см. п см. Примечания [ ] приняты во внимание следующие пункты: [ ] принята во внимание измененная формула изобретения (см. Примечания) 4. КЛАССИФИКАЦИЯ ОБЪЕКТА ИЗОБРЕТЕНИЯ (ПОЛЕЗНОЙ МОДЕЛИ) (Указываются индексы МПК и индикатор текущей версии) АО1К 67/027 (2006.01) 5. ОБЛАСТЬ ПОИСКА 5.1 Проверенный минимум документации РСТ (указывается индексами МПК) АОТК 67/027 5.2 Другая проверенная документация в той мере, в какой она включена в поисковые подборки: 5.3 Электронные базы данных, использованные при поиске (название базы, и если, возможно, поисковые термины): Е-Габгагу, Езрасепе, РаЗеагсв, РАТЕМТЗСОРЕ, КУРТО, Соозе, боозе Эсво]аг, РиБМеа, ОРТО, 5аепсе)иеси 6. ДОКУМЕНТЫ, ОТНОСЯЩИЕСЯ К ПРЕДМЕТУ ПОИСКА Кате- Наименование документа с указанием (где необходимо) ...

ВЫСОКОГЛИКОЗИЛИРОВАННЫЙ СЛИТЫЙ БЕЛОК НА ОСНОВЕ ФАКТОРА СВЕРТЫВАНИЯ КРОВИ ЧЕЛОВЕКА VIII, СПОСОБ ЕГО ПОЛУЧЕНИЯ И ЕГО ПРИМЕНЕНИЕ

Изобретение относится к области биотехнологии, конкретно к получению высокогликозилированных слитых белков на основе фактора свертывания крови человека VIII (FVIII), и может быть использовано в медицине для предупреждения или лечения геморрагических болезней у пациентов с дефицитом FVIII. Предложенный гомодимерный слитый белок состоит из, последовательно от N- к C-концу, фактора свертывания крови человека VIII, гибкого пептидного линкера, по меньшей мере одного жесткого карбокси-терминального пептидного звена бета-субъединицы хорионического гонадотропина человека и Fc-фрагмента иммуноглобулина человека. Изобретение позволяет получить белок с уровнем биологической активности, аналогичным уровню рекомбинантного FVIII, и продленным периодом полужизни in vivo, т.е. лекарственное средство на основе FVIII с улучшенной фармакокинетикой и эффективностью. 7 н. и 4 з.п. ф-лы, 5 ил., 3 табл.

ЖИВОТНЫЕ, ОТЛИЧНЫЕ ОТ ЧЕЛОВЕКА, С НАРУШЕНИЕМ В ЛОКУСЕ C9ORF72

Tiermodell für das humane Immunsystem, sowie Verfahren zu dessen Herstellung

Verfahren zur Herstellung eines Tiermodells für das humane Immunsystem in einem nicht-humanem Säugetier, mit den Schritten: a) Transplantation von humanen Stammzellen mit hämatopoetischen Potential in das nicht-humane Säugetier und b) Konditionieren des nicht-humanen Säugetiers mit Zellkulturüberstand einer Kultur von Zellinien, Zellen und/oder Gewebe, wobei der Zellkulturüberstand die humanen Faktoren Interleukin-8, Interleukin-6, und vaskulo-endothelialen Wachstumsfaktor (VEGF), Interferon-γ-induziertes Protein 10 (IP-10), Monozyten Chemotaktisches Protein-1 (MCP-1), Angiogenin und Gewebs-Plasminogen Aktivator (tPA) enthält.

TIERMODELL FÜR TYP III ALLERGISCHE ENTZÜNDUNGEN

Bildung von xenogenen Antikörpern

Highly glycosylated human blood-clotting factor VIII fusion protein, and manufacturing method and application of same

A highly glycosylated human blood-clotting factor VIII (FVIII) fusion protein, and a manufacturing method and application of same. The fusion protein comprises, from the N-terminus to the C-terminus, a human (FVIII), a flexible peptide connector, at least one rigid unit of a human chorionic gonadotropin β-subunit carboxyl terminal peptide, and a half-life extending portion (preferentially selected from a human IgG Fc variant). The fusion protein has a similar level of biological activity as a recombinant (FVIII) and an extended in vivo half-life, thereby improving pharmacokinetics and drug efficacy.

PRODUCTION AND USE OF TRANSGENEN MICE WITH MISSING EXPRESSION OF CD28

A HUMAN T-ZELL RECEPTOR THAT PROTEIN g COUPLED RECEPTOR FAMILY

MODIFIED LIGANDS FOR THE TIE-2-REZEPTOR

TRANSGENE MICE AS MODEL FOR OF MAIN CELLS OUTGOING ONE HUMAN ONE OF DISEASE PICTURES

INHIBIERUNG THE GROWTH OF SELECTED TUMORS WITH REKOMBINANTEN VIRUS VECTORS

FORMATION OF XENOGENEN ANTIBODIES

BAFF, ITS INHIBITORS AND ITS USE FOR MODULATING THE B-CELL-ANSWER

Il-21 as a regulator of immunoglobin production

Modified tie-2-receptor ligands

Transformant of nonprimatial mammal having serotype of advanced primate expressed by foreign gene transduction and process for producing the same

Transgenic animals comprising a humanized immune system

Tolerance to natural antibody antigens

Transgenic mammal capable of facilitating production of donor-specific functional immunity

Genetically modified mice and engraftment

A mouse with a humanization of the mIL-3 gene and the mGM-CSF gene, a knockout of a mRAG gene, and a knockout of a mIl2rg subunit gene; and optionally a humanization of the TPO gene is described. A RAG/Il2rg KO/hTPO knock-in mouse is described. A mouse engrafted with human hematopoietic stem cells (HSCs) that maintains a human immune cell (HIC) population derived from the HSCs and that is infectable by a human pathogen, e.g., S. typhi or M. tuberculosis is described. A mouse that models a human pathogen infection that is poorly modeled in mice is described, e.g., a mouse that models a human mycobacterial infection, wherein the mouse develops one or more granulomas comprising human immune cells. A mouse that comprises a human hematopoietic malignancy that originates from an early human hematopoietic cells is described, e.g., a myeloid leukemia or a myeloproliferative neoplasia.

Genetically modified non-human animals expressing human EPO

Genetically modified non-human animals expressing human EPO from the animal genome are provided. Also provided are methods for making non-human animals expressing human EPO from the non-human animal genome, and methods for using non-human animals expressing human EPO from the non-human animal genome. These animals and methods find many uses in the art, including, for example, in modeling human erythropoiesis and erythrocyte function; in modeling human pathogen infection of erythrocytes; in ...

Genetically modified non-human animals and methods of use thereof

... 1:\Interwovn\NRPortbl\DCC\FMT179005_I.DOCX-13/08/2019 The invention relates generally to genetically modified non-human animals expressing human polypeptides and their methods of use.

HUMAN ARTIFICIAL CHROMOSOME CONTAINING HUMAN ANTIBODY GHT CHA IN GENE

A human artificial chromosome which can be transferred to offspring (the next generation) at a high efficiency and method of using the same. Namely, a human artificial chromosome wherein a domain of about 3.5 Mb to about 1 Mb containing an antibody light chain gene originating in the human 22nd chromosome is ligated to a chromosome fragment originating in another human chromosome, which can be transferred to offspring, via a nonhuman animal genital system; a nonhuman animal carrying this artificial human chromosome and its offspring; a method of constructing the nonhuman animal; a method of constructing a human antibody using the nonhuman animal or its offspring; and a human antibody-producing mouse having the above artificial human chromosome.

BAFF, INHIBITORS THEREOF AND THEIR USE IN THE MODULATION OF B-CELL RESPONSE

... ▓▓▓The invention provides methods for treating or preventing disorders associated ▓with expression of BAFF comprising BAFF and fragments thereof, antibodies, ▓agonists and antagonists.▓ ...

NONHUMAN MODEL ANIMAL LACKING THE ABILITY TO CONTROL LYMPHOCYTE MIGRATION

It is intended to provide a model animal which is useful in identifying a molecule specifically controlling the mobility of lymphocytes and thus clarifying the pathogenic conditions at the molecular level of immunological diseases such as allergy, autoimmune diseases, GvH and graft rejection, or developing a novel therapy. A model animal such as a DOCK2 knockout mouse, in which the function of controlling lymphocyte migration has been deleted or regulated, is constructed by deleting DOCK2 gene on chromosome. In this DOCK2 knockout mouse, the function of activating Rac to thereby promote the reconstruction of actin cell skeleton, the lymphocyte migration function due to the stimuli with chemokines such as SLC, SDF-1 and BLC, the homing function toward secondary lymph tissues such as spleen, lymph nodes and Peyer~s patch and the function of releasing matured thymus T cells into peripheral blood are injured and, as a result, immune responses are regulated.

THE PRODUCTION AND USE OF RED BLOOD CELLS

MODIFIED TIE-2-RECEPTOR LIGANDS

TRANSGENIC ANIMALS HAVING A MODIFIED GLYCOPROTEIN V GENE

The present invention relates to nonhuman transgenic animals in which the GP V gene has been modified. The invention is also useful for identifying agents that modulate the biological functions of GP V, including the screening and identification of potential therapeutic agents.

TRANSGENIC ANIMAL MODEL OF IGE-MEDIATED ALLERGIC RESPONSES

L'invention se rapporte à une cellule animale non humaine transgénique, caractérisée en ce qu'elle exprime au moins une séquence nucléotidique codant pour au moins une des chaînes des récepteurs humains au fragment Fc~ des immunoglobulines IgE (Fc~.epsilon.R)) et une séquence nucléotidique codant pour la chaîne lourde des IgE dont au moins tout ou partie du fragment Fc~ est d'origine humaine, et caractérisée en ce que le gène murin codant pour la chaîne Fc.epsilon.)R) du récepteur humain est inactif. L'invention concerne l'animal transgénique correspondant ainsi que le procédé pour la compréhension des éléments physiopathologiques impliqués dans les mécanismes d'hypersensibilité immédiate et/ou inflammatoire. L'invention porte également sur un procédé de criblage de composés actifs envers les interactions entre les IgE humaines et leurs récepteurs.

NON-HUMAN ANIMALS HAVING A DISRUPTION IN A C9ORF72 LOCUS

A non-human animal model for neurodegenerative and/or inflammatory diseases is provided, which non-human animal comprises a disruption in a C9ORF72 locus. In particular, non-human animals described herein comprise a deletion of an entire coding sequence of a C9ORF72 locus. Methods of identifying therapeutic candidates that may be used to prevent, delay or treat one or more neurodegenerative (e.g., amyotrophic lateral sclerosis (ALS, also referred to as Lou Gehrig's disease) and frontotemporal dementia (FTD)), autoimmune and/or inflammatory diseases (e.g., SLE, glomerulonephritis) are also provided.

MODULATION OF BCL11A FOR TREATMENT OF HEMOGLOBINOPATHIES

The invention relates to methods and uses of modulating fetal hemoglobin expression (HbF) in a hematopoietic progenitor cells via inhibitors of BCL11A expression or activity, such as RNAi and antibodies.

GENETICALLY MODIFIED MICE AND ENGRAFTMENT

A mouse with a humanization of the mIL-3 gene and the mGM-CSF gene, a knockout of a mRAG gene, and a knockout of a mIl2rg subunit gene; and optionally a humanization of the TPO gene is described. A RAG/Il2rg KO/hTPO knock-in mouse is described. A mouse engrafted with human hematopoietic stem cells (HSCs) that maintains a human immune cell (HIC) population derived from the HSCs and that is infectable by a human pathogen, e.g., S. typhi or M. tuberculosis is described. A mouse that models a human pathogen infection that is poorly modeled in mice is described, e.g., a mouse that models a human mycobacterial infection, wherein the mouse develops one or more granulomas comprising human immune cells. A mouse that comprises a human hematopoietic malignancy that originates from an early human hematopoietic cells is described, e.g., a myeloid leukemia or a myeloproliferative neoplasia.

NON-HUMAN ANIMALS HAVING A HUMANIZED B-CELL ACTIVATING FACTOR GENE

Non-human animals, cells, methods and compositions for making and using the same are provided, wherein the non-human animals and cells comprise a humanized B-cell activating factor gene. Non-human animals and cells that express a human or humanized B-cell activating factor protein from an endogenous B-cell activating factor locus are described.

NON-HUMAN ANIMALS HAVING A HUMANIZED B-CELL ACTIVATING FACTOR GENE

Non-human animals, cells, methods and compositions for making and using the same are provided, wherein the non-human animals and cells comprise a humanized B-cell activating factor gene. Non-human animals and cells that express a human or humanized B-cell activating factor protein from an endogenous B-cell activating factor locus are described.

HOMOLOGOUS RECOMBINATION FOR UNIVERSAL DONOR CELLS AND CHIMERIC MAMMALIAN HOSTS

Homologous recombination is employed to inactivate genes, particularly genes associated with MHC antigens. Particularly, the .beta.2-microglobulin gene is inactivated for reducing or eliminating the expression of functional Class I MHC antigens. The resulting cells may be used as universal donor cells. In addition, embryonic stem cells may be modified by homologous recombination for use in producing chimeric or transgenic mammalian hosts, which may be used as source of universal donor organs, or as models for drug and transplantation therapies. Methods for homologous recombination in non-transformed mammalian somatic cells are also described.

LYMPHOID ANTIGEN CD30

The lymphoid surface antigen CD 30 (Ki-1) that appears during Hodgkin's disease, its protein sequence and corresponding nucleotide sequenc e, its production by genetic engineering, means for diagnosing and examining Hodgkin's disease, as well as the use of these nucleotide sequences to creat e transgenic animals are disclosed. The invention makes available means for examining and diagnosing anaplastic large-cell lymphomes that are not based on monoclonal antibodies.

NOVEL CTLA4/CD28 LIGANDS AND USES THEREFOR

Nucleic acids encoding novel CTLA4/CD28 ligands which costimulate T cell activation are disclosed. In one embodiment, the nucleic acid has a sequence which encodes a fusion protein consisting of at least part of the B lymphocyte antigen, B7-2, fused to one or more constant domains of immunoglobulin heavy chain. Preferably, the nucleic acid is a DNA molecule comprising at least a portion of a nucleotide sequence shown in Figure 8, SEQ ID NO:1 or Figure 14, SEQ ID NO:22. The nucleic acid sequences of the invention can be integrated into various expression vectors, which in turn direct the synthesis of the corresponding proteins or peptides in a variety of hosts, particularly eukaryotic cells, such as mammalian and insect cell culture. Also disclosed are host cells transformed to produce proteins or peptides encoded by the nucleic acid sequences of the invention and isolated proteins and peptides which comprise at least a portion of a novel B lymphocyte antigen. Proteins and peptides described ...

AMPLIFIER AND SILENCER SEQUENCES ISOLATED FROM THE GPIIB PROMOTER, AND APPLICATIONS THEREOF.

CELLS AND ANIMAL TRANSGENIQUES Of STUDY OF the POLARIZATION Of the REPONSEIMMUNE

Genetically modified mice and engraftment

A mouse with a humanization of the mIL-3 gene and the mGM-CSF gene, a knockout of a mRAG gene, and a knockout of a mII2rg subunit gene; and optionally a humanization of the TPO gene is described. A RAG/II2rg KO/hTPO knock-in mouse is described. A mouse engrafted with human hematopoietic stem cells (HSCs) that maintains a human immune cell (HIC) population derived from the HSCs and that is infectable by a human pathogen, e.g., S. typhi or M. tuberculosis is described. A mouse that models a human pathogen infection that is poorly modeled in mice is described, e.g., a mouse that models a human mycobacterial infection, wherein the mouse develops one or more granulomas comprising human immune cells. A mouse that comprises a human hematopoietic malignancy that originates from an early human hematopoietic cells is described, e.g., a myeloid leukemia or a myeloproliferative neoplasia.

Methods of Modulating Thrombocytopenia and Modified Transgenic Pigs

The application provides methods of modulating platelet uptake by liver sinusoidal endothelial cells and of modulating thrombocytopenia. Transgenic pigs modified to bind fewer platelets are provided.

Genetically Modified Mice and Engraftment

A mouse with a humanization of the mIL-3 gene and the mGM-CSF gene, a knockout of a mRAG gene, and a knockout of a mIl2rg subunit gene; and optionally a humanization of the TPO gene is described. A RAG/Il2rg KO/hTPO knock-in mouse is described. A mouse engrafted with human hematopoietic stem cells (HSCs) that maintains a human immune cell (HIC) population derived from the HSCs and that is infectable by a human pathogen, e.g., S. typhi or M. tuberculosis is described. A mouse that models a human pathogen infection that is poorly modeled in mice is described, e.g., a mouse that models a human mycobacterial infection, wherein the mouse develops one or more granulomas comprising human immune cells. A mouse that comprises a human hematopoietic malignancy that originates from an early human hematopoietic cells is described, e.g., a myeloid leukemia or a myeloproliferative neoplasia.

Genetically Modified Mice and Engraftment

A mouse with a humanization of the mIL-3 gene and the mGM-CSF gene, a knockout of a mRAG gene, and a knockout of a mIl2rg subunit gene; and optionally a humanization of the TPO gene is described. A RAG/Il2rg KO/hTPO knock-in mouse is described. A mouse engrafted with human hematopoietic stem cells (HSCs) that maintains a human immune cell (HIC) population derived from the HSCs and that is infectable by a human pathogen, e.g., or is described. A mouse that models a human pathogen infection that is poorly modeled in mice is described, e.g., a mouse that models a human mycobacterial infection, wherein the mouse develops one or more granulomas comprising human immune cells. A mouse that comprises a human hematopoietic malignancy that originates from an early human hematopoietic cells is described, e.g., a myeloid leukemia or a myeloproliferative neoplasia. 117.-. (canceled)18. A method comprising:engrafting a second mouse with human hematopoietic cells isolated from a genetically modified first mouse, wherein the genetically modified first mouse is immunocompromised for a mouse immune system, wherein the genetically modified first mouse comprises an engraftment of human hematopoietic cells and a replacement of each allele of the mouse thrombopoietin (TPO) gene with a human TPO gene at the mouse TPO gene locus, and wherein the second mouse is immunocompromised for a mouse immune system.19. The method of claim 18 , wherein the human hematopoietic cells comprise CD34+ cells.20. The method of claim 18 , wherein the first mouse comprises a replacement of a mouse IL-3 gene with a human IL-3 gene at a mouse IL-3 gene locus claim 18 , and a replacement of a mouse GM-CSF gene with a human GM-CSF gene at a mouse GM-CSF gene locus.21. The method of claim 18 , wherein the first mouse is null for a RAG2 gene claim 18 , and null for a mouse interleukin 2 receptor gamma (IL-2Rg) gene.22. The method of claim 18 , wherein the second mouse comprises a replacement of a mouse IL-3 gene ...

Genetically Modified Non-Human Animals And Methods Of Use Thereof

The invention relates generally to genetically modified non-human animals expressing human polypeptides and their methods of use. 1. A genetically modified mouse comprising in its genome:a recombination activating gene 2 (Rag-2) gene knock-out;an IL2 receptor gamma chain (IL2rg) gene knock-out;a replacement of a mouse M-CSF gene with a nucleic acid encoding a human M-CSF polypeptide, wherein the nucleic acid encoding the human M-CSF polypeptide is operably linked to a M-CSF promoter at a mouse M-CSF gene locus;a replacement of a mouse IL-3 gene with a nucleic acid encoding a human IL-3 polypeptide, wherein the nucleic acid encoding the human IL-3 polypeptide is operably linked to a IL-3 promoter at a mouse IL-3 gene locus;a replacement of a mouse GM-CSF gene with a nucleic acid encoding a human GM-CSF polypeptide, wherein the nucleic acid encoding the human GM-CSF polypeptide is operably linked to a GM-CSF promoter at a mouse GM-CSF gene locus;a replacement of a mouse-SIRPA gene with a nucleic acid encoding a fusion protein comprising a biologically active fragment of a full length human SIRPA polypeptide, wherein the nucleic acid encoding the fusion protein is operably linked to a SIRPA promoter; anda replacement of a mouse TPO gene with a nucleic acid encoding a human TPO polypeptide, wherein the nucleic acid encoding the human TPO polypeptide is operably linked to a TPO promoter at a mouse TPO gene locus, wherein the mouse expresses the human M-CSF polypeptide, the human IL-3 polypeptide, the human GM-CSF polypeptide, the fusion protein, and the human TPO polypeptide.28.-. (canceled)9. The genetically modified mouse of claim 1 , further comprising human hematopoietic cells.10. The genetically modified mouse of claim 1 , further comprising a human cancer cell.11. The genetically modified mouse of claim 10 , wherein the human cancer cell is a leukemia cell or a melanoma cell.12. A method of hematopoietic stem and progenitor cell (HSPC) engraftment in a genetically ...

Human SIRPa Transgenic Animals and Their Methods of Use

The invention relates generally to compositions and methods of using transgenic non-human animals expressing human SIRPα that are engrafted with a human hematopoietic system. In various embodiments, the human hematopoietic system engrafted, human SIRPα transgenic non-human animals of the invention are useful as systems for the in vivo evaluation of the growth and differentiation of hematopoietic and immune cells, for the in vivo assessment of an immune response, for the in vivo evaluation of vaccines and vaccination regimens, for in vivo production and collection of immune mediators, including human antibodies, and for use in testing the effect of agents that modulate hematopoietic and immune cell function.

METHODS OF A DROSOPHILA MODEL FOR CHRONIC MYELOID LEUKEMIA (CML) TREATMENT

As disclosed herein, the invention relates to a method of screening for a therapeutic for chronic myeloid leukemia. In an aspect, the invention relates to transgenic Drosophila. In an aspect, the invention relates to a Drosophila system for screening compounds treating chronic myeloid leukemia. 1. An in vivo method of screening for a therapeutic for chronic myeloid leukemia , the method comprising: administering a candidate therapeutic for chronic myeloid leukemia to Drosophila larvae , wherein the larvae express a human BCR-ABL transgene; determining the survival of the larvae/pupae to a further developmental stage; and the survival of the larvae/pupae indicates that the candidate therapeutic for chronic myeloid leukemia is a therapeutic for chronic myeloid leukemia.2. The method of claim 1 , wherein the human BCR-ABL transgene comprises one or more mutations.3. The method of claim 1 , wherein the therapeutic for chronic myeloid leukemia ameliorates one or more signs or symptoms associated with chronic myeloid leukemia.4. The method of claim 3 , wherein the one or more signs or symptoms associated with chronic myeloid leukemia comprises phenotypic signs or symptoms.5. The method of claim 1 , further comprising examining eye and lethality phenotypes or a combination thereof.6. A transgenic Drosophila comprising a human BCR-ABL gene.7. The transgenic Drosophila of claim 6 , wherein the BCR-ABL gene comprises one or more mutations.8. The transgenic Drosophila of claim 6 , and a therapeutic for CML identified by the transgenic Drosophila.9. An in vivo method of screening for a therapeutic for CML claim 6 , the method comprising: administering a candidate therapeutic for CML to Drosophila larvae claim 6 , wherein the larvae express a human BCR-ABL and a p210transgene; and determining the rough eye phenotype (particularly the presence or absence of an eye groove); and the reversal of the rough eye phenotype (particularly the restoration of ommatidial development in the ...

Non-human animals having a humanized signal-regulatory protein gene

Genetically modified non-human animals and methods and compositions for making and using the same are provided, wherein the genetic modification comprises a humanization of an endogenous signal-regulatory protein gene, in particular a humanization of a SIRPα gene. Genetically modified mice are described, including mice that express a human or humanized SIRPα protein from an endogenous SIRPα locus.

PRODUCTION AND USE OF RED BLOOD CELLS

The present disclosure relates to the production of red blood cells from hematopoietic stem cells, by differentiating such cells in the presence of a protein that induces cell survival and proliferation. 165.-. (canceled)66. A method for treating a disease or disorder characterized by a deficiency of anucleated red blood cells in a subject in need thereof comprising:(a) culturing a population of hematopoietic stem cells in a differentiation media comprising erythropoietin (EPO) and a recombinant fusion protein comprising a MYC polypeptide fused to a protein transduction domain, wherein culturing the hematopoietic stem cells induces differentiation of the hematopoietic stem cells to mature red blood cells, thereby producing a population of mature red blood cells; and(b) administering to the subject the population of mature red blood cells.67. The method of claim 66 , wherein the recombinant fusion protein is TAT-MYC.68. The method of claim 66 , wherein the differentiation media further comprises one or more recombinant proteins that inhibit apoptosis claim 66 , wherein the one or more recombinant proteins that inhibit apoptosis comprises one or more Bcl2 homology domains selected from the group consisting of BH1 claim 66 , BH2 claim 66 , BH3 claim 66 , and BH4.69. The method of claim 66 , wherein the hematopoietic stem cells further comprise one or more recombinant proteins of interest.70. The method of claim 66 , wherein the hematopoietic stem cells comprise one or more transgenes that encode one or more recombinant proteins of interest.71. The method of claim 70 , wherein the expression or function of the one or more recombinant proteins of interest is controllable or inducible.72. The method of claim 66 , wherein the disease or disorder characterized by a deficiency of anucleated red blood cells is selected from one or more of anemia claim 66 , Gaucher's disease claim 66 , hemolysis claim 66 , neutropenia claim 66 , thrombocytopenia claim 66 , granulocytopenia ...

SCREENING METHOD FOR SELECTED AMINO-LIPID-CONTAINING COMPOSITIONS

The invention features a method of identifying therapeutically relevant compositions which include a therapeutic agent and 2,2-dimethylaminomethyl-[1-3]-dioxolane by screening for an effect of the agent on the liver of a model subject. 1. A method of evaluating a composition that includes a therapeutic agent and 2 ,2-Dilinoley 1-4-dimethylaminomethyl-[1 ,3]-dioxolane comprising:providing a composition that includes a therapeutic agent and 2,2-Dilinoley 1-4-dimethylaminomethyl-[1,3]-dioxolane;administering the composition to a test animal; anddetermining the effect of the composition on the expression of a target gene expressed in the liver of the animal,thereby evaluating the composition.2. The method of claim 1 , wherein the therapeutic agent is an RNA-based construct.3. The method of claim 2 , wherein the RNA-based construct is a dsRNA.4. The method of claim 1 , wherein the target gene is Factor VII.5. The method of claim 1 , wherein determining the effect of the composition comprises determining target protein levels.6. The method of claim 1 , wherein determining the effect of the composition comprises determining target mRNA levels.7. The method of claim 5 , wherein the level of target protein in blood is determined.8. The method of claim 6 , wherein the level of target mRNA in liver is determined.9. The method of claim 1 , further comprising comparing expression of the target gene with a preselected reference value.10. The method of claim 1 , wherein the composition further comprises a third component.11. The method of claim 1 , wherein the therapeutic agent is an antisense RNA claim 1 , ribozyme or microRNA.12. The method of claim 1 , wherein the test animal is a rodent.13. The method of claim 1 , wherein the test animal is a mouse.14. The method of claim 1 , wherein the composition reduces FVII protein or mRNA levels in the blood.15. The method of claim 1 , wherein the composition reduces FVII protein or mRNA levels in the liver.16. The method of claim 1 , ...

GENETICALLY MODIFIED NON-HUMAN ANIMALS EXPRESSING HUMAN EPO

Genetically modified non-human animals expressing human EPO from the animal genome are provided. Also provided are methods for making non-human animals expressing human EPO from the non-human animal genome, and methods for using non-human animals expressing human EPO from the non-human animal genome. These animals and methods find many uses in the art, including, for example, in modeling human erythropoiesis and erythrocyte function; in modeling human pathogen infection of erythrocytes; in in vivo screens for agents that modulate erythropoiesis and/or erythrocyte function, e.g. in a healthy or a diseased state; in in vivo screens for agents that are toxic to erythrocytes or erythrocyte progenitors; in in vivo screens for agents that prevent against, mitigate, or reverse the toxic effects of toxic agents on erythrocytes or erythrocyte progenitors; in in vivo screens of erythrocytes or erythrocyte progenitors from an individual to predict the responsiveness of an individual to a disease therapy. 158.-. (canceled)59. A genetically modified mouse , comprising:a nucleic acid sequence that encodes a human erythropoietin (hEPO) protein operably linked to an endogenous mouse erythropoietin (EPO) gene promoter at the mouse EPO gene locus in the genome of the genetically modified mouse, wherein the mouse expresses the hEPO protein;a nucleic acid sequence that encodes a human interleukin 3 (hlL3) protein operably linked to an endogenous interleukin 3 (IL-3) gene promoter at the mouse IL-3 gene locus in the genome of the genetically modified mouse, wherein the mouse expresses the hlL3 protein;a nucleic acid sequence that encodes a human granulocyte-macrophage colony stimulating factor 2 (hGM-CSF) protein operably linked to an endogenous granulocyte-macrophage colony stimulating factor (GM-CSF) gene promoter at the mouse GM-CSF gene locus in the genome of the genetically modified mouse, wherein the mouse expresses the hGM-CSF protein;a nucleic acid sequence that encodes a human ...

Genetically Modified Non-Human Animals And Methods Of Use Thereof

The invention relates generally to genetically modified non-human animals expressing human polypeptides and their methods of use. 127.-. (canceled)28. A method of transplanting human cancer cells , comprising:transplanting human cancer cells into a genetically modified, immunodeficient mouse; andtransplanting human hematopoietic cells into the genetically modified, immunodeficient mouse,wherein the genetically modified, immunodeficient mouse comprises in its genome a recombination activating gene 2 (Rag-2) gene knock-out, an IL2 receptor gamma chain (IL2rg) gene knock-out, a replacement of a mouse M-CSF gene with a nucleic acid encoding a human M-CSF polypeptide at a mouse M-CSF gene locus, a replacement of a mouse IL-3 gene with a nucleic acid encoding a human IL-3 polypeptide at a mouse IL-3 gene locus, a replacement of a mouse GM-CSF gene with a nucleic acid encoding a human GM-CSF polypeptide at a mouse GM-CSF gene locus, an insertion of a nucleic acid encoding a human SIRPA polypeptide, and a replacement of a mouse TPO gene with a nucleic acid encoding a human TPO polypeptide at a mouse TPO gene locus, wherein each of the nucleic acids encoding the human M-CSF polypeptide, the human IL-3 polypeptide, the human GM-CSF polypeptide, the human SIRPA polypeptide, and the human TPO polypeptide is operably linked to a promoter, and wherein the mouse expresses the human M-CSF polypeptide, the human IL-3 polypeptide, the human GM-CSF polypeptide, the human SIRPA polypeptide, and the human TPO polypeptide.29. The method of claim 28 , wherein the human cancer cells are primary human cancer cells isolated from a patient.30. The method of claim 29 , wherein the human cancer cells and the human hematopoietic cells are isolated from the same patient.31. The method of claim 28 , wherein the human cancer cells are from a cancer cell line.32. The method of claim 28 , wherein the human cancer cells are selected from leukemia cells claim 28 , breast cancer cells claim 28 , lung ...

Genetically Modified Non-Human Animals And Methods Of Use Thereof

The invention relates generally to genetically modified non-human animals expressing human polypeptides and their methods of use. 127.-. (canceled)28. A method for in vivo evaluation of a vaccine , the method comprising: a recombination activating gene 2 (Rag-2) gene knock-out,', 'an IL2 receptor gamma chain (IL2rg) gene knock-out,', 'a replacement of a mouse M-CSF gene with a nucleic acid encoding a human M-CSF polypeptide at a mouse M-CSF gene locus,', 'a replacement of a mouse IL-3 gene with a nucleic acid encoding a human IL-3 polypeptide at a mouse IL-3 gene locus,', 'a replacement of a mouse GM-CSF gene with a nucleic acid encoding a human GM-CSF polypeptide at a mouse GM-CSF gene locus,', 'a replacement of a mouse TPO gene with a nucleic acid encoding a human TPO polypeptide at a mouse TPO gene locus, and', 'an insertion of a nucleic acid encoding a human SIRPα polypeptide,', 'wherein each of the nucleic acids encoding the human M-CSF polypeptide, the human IL-3 polypeptide, the human GM-CSF polypeptide, the human SIRPα polypeptide, and the human TPO polypeptide is operably linked to a promoter,', 'wherein the mouse expresses the human M-CSF polypeptide, the human IL-3 polypeptide, the human GM-CSF polypeptide, the human SIRPA polypeptide, and the human TPO polypeptide, and', 'wherein the mouse is engrafted with human hematopoietic cells; and, 'administering a vaccine to a genetically modified mouse, wherein the genetically modified mouse comprises in its genomeassessing an immune response to the vaccine in the genetically modified mouse.29. The method of claim 28 , wherein the human hematopoietic cells comprise hematopoietic stem cells (HSCs).30. The method of claim 28 , wherein the human hematopoietic cells comprise hematopoietic stem and progenitor cells (HSPCs).31. The method of claim 28 , wherein the mouse is not sub-lethally irradiated prior to the engraftment of the human hematopoietic cells.32. A method for in vivo evaluation of a vaccine claim 28 , ...

NON-HUMAN ANIMALS HAVING A HUMANIZED SIGNAL-REGULATORY PROTEIN GENE

Genetically modified non-human animals and methods and compositions for making and using the same are provided, wherein the genetic modification comprises a humanization of an endogenous signal-regulatory protein gene, in particular a humanization of a SIRPα gene. Genetically modified mice are described, including mice that express a human or humanized SIRPα protein from an endogenous SIRPα locus. 153.-. (canceled)54. A rodent whose genome comprises a humanized SIRPα gene at an endogenous rodent SIRPα locus , wherein the humanized SIRPα gene(i) comprises exon 1 of a rodent SIRPα gene, exons 2, 3 and 4 of a human SIRPα gene, and exons 5, 6, 7 and 8 of the rodent SIRPα gene,(ii) is operably linked to a rodent SIRPα promoter at the endogenous rodent SIRPα locus, and(iii) expresses in the rodent a humanized SIRPα protein comprising an extracellular portion of the human SIRPα protein encoded by the human SIRPα gene and an intracellular portion of the rodent SIRPα protein encoded by the rodent SIRPα gene; andwherein the rodent is a rat.55. The rodent of claim 54 , wherein the extracellular portion of the human SIRPα protein comprises amino acid residues 28-362 of the human SIRPα protein.56. The rodent of claim 54 , wherein the human SIRPα protein comprises the amino acid sequence as set forth in SEQ ID NO: 4.57. The rodent of claim 54 , and wherein the rodent is homozygous for the humanized SIRPα gene.58. The rodent of claim 54 , wherein the rodent does not express an endogenous rodent SIRPα protein.59. A rodent embryonic stem (ES) cell claim 54 , comprising a humanized SIRPα gene at an endogenous rodent SIRPα locus claim 54 , wherein the humanized SIRPα gene(i) comprises exon 1 of a rodent SIRPα gene, exons 2, 3 and 4 of a human SIRPα gene, and exons 5, 6, 7 and 8 of the rodent SIRPα gene,(ii) is operably linked to a rodent SIRPα promoter at the endogenous rodent SIRPα locus, and(iii) encodes a humanized SIRPα protein comprising an extracellular portion of the human SIRP ...

Non-human animals having a humanized b-cell activating factor gene

Non-human animals, cells, methods and compositions for making and using the same are provided, wherein the non-human animals and cells comprise a humanized B-cell activating factor gene. Non-human animals and cells that express a human or humanized B-cell activating factor protein from an endogenous B-cell activating factor locus are described.

NON-HUMAN ANIMALS HAVING A HUMANIZED CLUSTER OF DIFFERENTIATION 47 GENE

Non-human animals, and methods and compositions for making and using the same, are provided, wherein said non-human animals comprise a humanization of an endogenous cluster of differentiation (CD) gene, in particular a humanization of a CD47 gene. Said non-human animals may be described, in some embodiments, as having a genetic modification to an endogenous CD47 gene so that said non-human animals express a CD47 polypeptide that includes a human portion and a non-human portion (e.g., a murine portion). 1. A rodent comprising a CD47 gene that comprises an endogenous portion and a human portion , wherein the endogenous and human portions are operably linked to an endogenous CD47 promoter.2. The rodent of claim 1 , wherein the endogenous portion comprises exons 1 and the exons downstream of exon 7 of an endogenous CD47 gene.3. The rodent of claim 2 , wherein exons 1 and the exons downstream of exon 7 of the endogenous CD47 gene are at least 90% claim 2 , or at least 95% claim 2 , identical to the corresponding exons 1 and and the exons downstream of exon 7 of a mouse CD47 gene that appears in Table 3.4. The rodent of any one of - claim 2 , wherein the human portion encodes amino acids 16-292 of a human CD47 polypeptide.5. The rodent of any one of - claim 2 , wherein the human portion comprises exons 2-7 of a human CD47 gene.6. The rodent of claim 5 , wherein exons 2-7 of the human CD47 gene are at least 50% identical to the corresponding exons 2-7 of a human CD47 gene that appears in Table 3.7. The rodent of claim 5 , wherein exons 2-7 of the human CD47 gene are at least 60% identical to the corresponding exons 2-7 of a human CD47 gene that appears in Table 3.8. The rodent of claim 5 , wherein exons 2-7 of the human CD47 gene are at least 70% identical to the corresponding exons 2-7 of a human CD47 gene that appears in Table 3.9. The rodent of claim 5 , wherein exons 2-7 of the human CD47 gene are at least 80% identical to the corresponding exons 2-7 of a human CD47 ...

NON-HUMAN ANIMALS HAVING A HUMANIZED SIGNAL-REGULATORY PROTEIN GENE

Genetically modified non-human animals and methods and compositions for making and using the same are provided, wherein the genetic modification comprises a humanization of an endogenous signal-regulatory protein gene, in particular a humanization of a SIRPα gene. Genetically modified mice are described, including mice that express a human or humanized SIRPα protein from an endogenous SIRPα locus. 1. A mouse expressing a SIRPα polypeptide comprising an extracellular portion of a human SIRPα protein and an intracellular portion of a mouse SIRPα protein.2. The mouse of claim 1 , wherein the extracellular portion of a human SIRPα protein comprises amino acids corresponding to residues 28-362 of a human SIRPα protein that appears in Table 3.3. The mouse of or claim 1 , wherein the extracellular portion of a human SIRPα protein shares a percent identity of at least 50% with a corresponding extracellular portion of a human SIRPα protein that appears in Table 3.4. The mouse of or claim 1 , wherein the shared percent identity is at least 60% with a corresponding extracellular portion of a human SIRPα protein that appears in Table 3.5. The mouse of or claim 1 , wherein the shared percent identity is at least 70% with a corresponding extracellular portion of a human SIRPα protein that appears in Table 3.6. The mouse of or claim 1 , wherein the shared percent identity is at least 80% with a corresponding extracellular portion of a human SIRPα protein that appears in Table 3.7. The mouse of or claim 1 , wherein the extracellular portion of a human SIRPα protein has a sequence that is at least 90% identical to an extracellular portion of a human SIRPα protein that appears in Table 3.8. The mouse of or claim 1 , wherein the extracellular portion of a human SIRPα protein has a sequence that is at least 95% identical to an extracellular portion of a human SIRPα protein that appears in Table 3.9. The mouse of or claim 1 , wherein the extracellular portion of a human SIRPα protein ...

Modulation of bcl11a for treatment of hemoglobinopathies

The invention relates to methods and uses of modulating fetal hemoglobin expression (HbF) in a hematopoietic progenitor cells via inhibitors of BCL11A expression or activity, such as RNAi and antibodies.

HUMAN LAMBDA LIGHT CHAIN MICE

Genetically modified mice are provided that express human λ variable (hVλ) sequences, including mice that express hVλ sequences from an endogenous mouse λ light chain locus, mice that express hVλ sequences from an endogenous mouse κ light chain locus, and mice that express hVλ, sequences from a transgene or an episome wherein the hVλ sequence is linked to a mouse constant sequence. Mice are provided that are a source of somatically mutated human λ variable sequences useful for making antigen-binding proteins. Compositions and methods for making antigen-binding proteins that comprise human λ variable sequences, including human antibodies, are provided. 120-. (canceled)21. A genetically modified mouse , whose genome comprises:(a) one or more unrearranged human Vλ gene segments,(b) one or more unrearranged human Jλ gene segments, and(c) one or more human Cλ gene segments,wherein the one or more unrearranged human Vλ gene segments of (a) and the one or more unrearranged human Jλ gene segments of (b) are at an endogenous mouse λ light chain locus.22. The genetically modified mouse of claim 21 , wherein the endogenous mouse λ light chain locus comprises one or more mouse Cλ gene segments.23. The genetically modified mouse of claim 22 , wherein the one or more mouse Cλ gene segments is one mouse Cλ gene segment.24. (canceled)25. The genetically modified mouse of claim 22 ,wherein the one or more unrearranged human Vλ gene segments of (a) and the one or more unrearranged human Jλ gene segments of (b) are operably linked to the one or more human Cλ gene segments of (c), andwherein the one or more unrearranged human Vλ gene segments of (a) and the one or more unrearranged human Jλ gene segments of (b) are operably linked to the one or more mouse Cλ gene segments.26. The genetically modified mouse of claim 21 , wherein the one or more human Cλ gene segments comprise at least four human Cλ gene segments.27. The genetically modified mouse of claim 21 , wherein the one or more ...

Transgenic Immunodeficient Mouse Expressing Human SIRP-alpha

The present invention provides a transgenic mouse which comprises a deficiency for murine T lymphocytes, B lymphocytes and NK cells, a deficiency for murine MHC class I and MHC class II molecules, and a functional xenogenic SIRPα transgene. This mouse is useful for in vivo screening of various compounds, including immuno-therapeutic agents and vaccines. The said mouse is also useful for testing the in vivo metabolism of xenobiotic compounds. 1. A transgenic mouse , said mouse having a phenotype comprising:a. a deficiency for murine T lymphocytes, B lymphocytes and NK cells,b. a deficiency for murine MHC class I and MHC class II molecules, andc. a functional xenogenic SIRPα transgene.2. A transgenic mouse , said mouse having a phenotype comprising:a. a deficiency for murine T lymphocytes, B lymphocytes and NK cells,b. a deficiency for murine MHC class I and MHC class II molecules,c. a functional xenogenic MHC class I transgene and/or a functional xenogenic MHC class II transgene, andd. a functional xenogenic SIRPα transgene.3. The transgenic mouse of any one of or , wherein the said mouse is from a non-permissive background.4. The transgenic mouse of claim 3 , wherein the said mouse is from a background which is neither NOD nor BALB/c.5. The transgenic mouse of any one of to claim 3 , wherein the deficiency in a) is associated with a deficient Rag2 gene and a deficient common receptor γ chain gene.6. The transgenic mouse of any one of to claim 3 , wherein the deficiency in murine MHC class I molecules is associated with a deficient β2-microglobulin gene.7. The transgenic mouse of any one of to claim 3 , wherein the deficiency in murine MHC class II molecules is associated with a deficient H-2-Aβ gene.8. The transgenic mouse of any one of to claim 3 , wherein the xenogenic MHC class I and/or class II transgenes are human HLA class I and/or HLA class II transgenes.9. The transgenic mouse of claim 8 , wherein the HLA class I transgene is an HLA-A2 transgene and the HLA ...

Human Lambda Light Chain Mice

Genetically modified mice are provided that express human λ variable (hVλ) sequences, including mice that express hVλ sequences from an endogenous mouse λ light chain locus, mice that express hVλ sequences from an endogenous mouse κ light chain locus, and mice that express hVλ sequences from a transgene or an episome wherein the hVλ sequence is linked to a mouse constant sequence. Mice are provided that are a source of somatically mutated human λ variable sequences useful for making antigen-binding proteins. Compositions and methods for making antigen-binding proteins that comprise human λ variable sequences, including human antibodies, are provided.

MODULATION OF BCL11A FOR TREATMENT OF HEMOGLOBINOPATHIES

The invention relates to methods and uses of modulating fetal hemoglobin expression (HbF) in a hematopoietic progenitor cells via inhibitors of BCL11A expression or activity, such as RNAi and antibodies. 1. A method for increasing fetal hemoglobin levels in a cell, the method comprising the steps of contacting a hematopoietic progenitor cell with an effective amount of a composition comprising an inhibitor of BCL11A, whereby fetal hemoglobin expression is increased in said cell, or its progeny, relative to said cell prior to said contacting. This application is a continuation application of U.S. patent application Ser. No. 15/888,350 filed on Feb. 5, 2018, which is a continuation application of U.S. patent application Ser. No. 14/987,219 filed on Jan. 4, 2016, issued as U.S. Pat. No. 9,885,041 on Feb. 6, 2018, which is a continuation application of U.S. patent application Ser. No. 13/743,399 filed on Jan. 17, 2013, issued as U.S. Pat. No. 9,228,185 on Jan. 5, 2016, which is a continuation application of U.S. patent application Ser. No. 13/063,524 filed on Apr. 14, 2011, issued as U.S. Pat. No. 8,383,604 on Feb. 26, 2013 and is a 35 U.S.C. § 371 National Phase Entry Application of International Application No. PCT/US2009/056770 filed Sep. 14, 2009, which designates the U.S., and which claims benefit under 35 U. S. C. § 119(e) of U.S. Provisional Application No. 61/097,017 filed on Sep. 15, 2008 and U.S. Provisional Application No. 61/222,571 filed on Jul. 2, 2009, the contents of each are incorporated herein by reference in their entireties.This invention was made with Government Support under T32 GM07726, T32 GM07753-27, 5P01 HL32262-26, and 5R01 HL32259-27, all awarded by the National Institutes of Health. The Government has certain rights in the invention.The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Feb. 11, 2019, is ...

PRODUCTION AND USE OF RED BLOOD CELLS

The present disclosure relates to the production of red blood cells from hematopoietic stem cells, by differentiating such cells in the presence of a protein that induces cell survival and proliferation. 165.-. (canceled)66. A method for extending the half-life of a population of mature red blood cells in vitro comprising:maintaining a population of red blood cells in a culture media comprising an exogenous polypeptide comprising one or more Bcl-2 homology domains.67. The method of claim 66 , wherein the one or more Bcl-2 homology domains are selected from the group consisting of BH1 claim 66 , BH2 claim 66 , BH3 claim 66 , and BH4.68. The method of claim 66 , wherein the exogenous polypeptide is one or more of Bcl-2 claim 66 , Bcl-w claim 66 , Bcl-X claim 66 , Bcl-XL claim 66 , or Mcl-1.69. The method of claim 66 , wherein the exogenous polypeptide is Bcl-2.70. The method of claim 66 , wherein the exogenous polypeptide comprises a protein transduction domain.71. The method of claim 70 , wherein the protein transduction domain is selected from the group consisting of TAT claim 70 , VPR claim 70 , and EPTD.72. The method of claim 71 , wherein the exogenous polypeptide is TAT-Bcl-2.73. The method of claim 66 , wherein the loss of one or more red blood cell functional characteristics is reduced claim 66 , as compared to maintaining a corresponding population of red blood cells in the absence of Bcl-2.74. The method of claim 73 , wherein the one or more functional characteristics is selected from among oxygen carrying capacity claim 73 , amount of hemoglobin claim 73 , type of hemoglobin expressed claim 73 , level of transferrin receptor expressed on the surface claim 73 , or level of one or more mature red blood cell markers.75. The method of claim 66 , wherein the population of red blood cells is produced by in vitro differentiation of hematopoietic stem cells.76. The method of claim 66 , wherein the population of red blood cells is obtained from peripheral blood of a ...

MODULATION OF BCL11A FOR TREATMENT OF HEMOGLOBINOPATHIES

The invention relates to methods and uses of modulating fetal hemoglobin expression (HbF) in a hematopoietic progenitor cells via inhibitors of BCL11A expression or activity, such as RNAi and antibodies. 1. A method for increasing fetal hemoglobin levels in a cell , the method comprising the steps of contacting a hematopoietic progenitor cell with an effective amount of a composition comprising an inhibitor of BCL11A , whereby fetal hemoglobin expression is increased in said cell , or its progeny , relative to said cell prior to said contacting.2. The method of claim 1 , wherein the hematopoietic progenitor cell is a cell of the erythroid lineage.3. The method of claim 1 , wherein the hematopoietic progenitor cell is contacted ex vivo or in vitro.4. The method of claim 1 , wherein the composition comprising an inhibitor of BCL11A inhibits BCL11A expression.5. The method of claim 4 , wherein the inhibitor of BCL11A expression is selected from a small molecule and a nucleic acid.6. The method of claim 5 , wherein the nucleic acid is a BCL11A specific RNA interference agent claim 5 , or a vector encoding a BCL11A specific RNA interference agent.7. The method of claim 6 , wherein said RNA interference agent comprises one or more of the nucleotide sequences of SEQ ID NO: 1-6.8. The method of claim 1 , wherein the composition comprising an inhibitor of BCL11A inhibits BCL11A activity.9. The method of claim 8 , wherein the inhibitor of BCL11A activity is selected from the group consisting of an antibody against BCL11A or an antigen-binding fragment thereof claim 8 , a small molecule claim 8 , and a nucleic acid.10. The method of claim 9 , wherein the nucleic acid is a BCL11A specific RNA interference agent claim 9 , a vector encoding a RNA interference agent claim 9 , or an aptamer that binds BCL11A.11. The method of claim 10 , wherein said RNA interference agent comprises one or more of the nucleotide sequences of SEQ ID NO: 1-6.12. A method for increasing fetal ...

Compositions and Methods of Treatment of Black Hemophiliac Patients

It has been determined that most mutations in factor VIII occur in multiple haplotypes, not primarily in one haplotype. The frequencies of mild, moderate, and severe hemophilia did not differ significantly according to the background haplotype. The odds of having inhibitor were significantly higher among patients in the H3+H4 haplotype groups as compared to H1+H2 haplotype groups. This association appears to be independent of the mutation. The results indicate that white hemophiliacs should be treated with Kogenate®. However, it would clearly be of benefit to assess the haplotype of black hemophiliacs prior to prescribing the recombinant FVIII to be used for treatment. It is not essential to determine the actual mutations responsible for the hemophilia prior to prescribing the recombinant FVIII. Also described are transgenic human FVIII animal models. 1. A transgenic animal expressing human FVIII.2. The animal of wherein the human FVIII has a haplotype selected from the group consisting of haplotype 1 claim 1 , 2 claim 1 , 3 claim 1 , 4 claim 1 , 5 claim 1 , 6 claim 1 , 7 and 8.3. The animal of wherein the FVIII contains an intron-22 inversion.4. The animal of wherein the human FVIII has a haplotype selected from the group consisting of haplotype 1 claim 3 , 2 claim 3 , 3 claim 3 , 4 claim 3 , 5 claim 3 , 6 claim 3 , 7 and 8. The Government has certain rights in the invention since the invention was made with support from Grant Nos. HL-71130 and HL-72533 to Dr. Howard; Grant No. HL-07109 to Dr. Thompson and HL-70751 to Dr. Almasy by the National Institutes of Health.The invention is generally in the field of diagnostic and therapeutics for hemophiliacs.Hemophilia is a congenital bleeding disorder. Patients with Hemophilia A have either absent, decreased or defective production of the blood clotting protein, Factor VIII (FVIII). Those with Hemophilia B have similar problems with Factor IX (FIX). Hemophilia is characterized as “severe” when the activity of the ...

MODELS OF THROMBOTIC THROMBOCYTOPENIC PURPURA AND METHODS OF USE THEREOF

The invention relates to the development of an animal model for testing various agents in the treatment of a clotting disorder. More specifically, the invention relates to the use of ultra-large molecular weight multimers of von Willebrand factor (VWF) in various mouse strains to induce thrombotic thrombocytopenic purpura (TTP)-like symptoms for the development of a mouse model of TTP. The invention also provides methods for generating such animal disease models and screening methods for identifying biologically active compounds which are effective in the treatment of TTP. 17-. (canceled)8. A method of testing an agent for its ability to reduce blood clotting in a mammal administered recombinant von Willebrand factor in an amount effective to cause mortality comprising comparing mortality rates in an animal model in the presence and absence of a test agent wherein decreased mortality in the presence of the test agent indicates that the test agent has the ability to reduce blood clotting.9. The method of claim 8 , wherein the animal model is deficient in a disintegrin and metalloprotease with thrombospondin type 1 domains 13 (ADAMTS13) polypeptide.10. The method of claim 9 , wherein the amount of recombinant von Willebrand factor is greater than 1000 RCoU/kg.11. The method of claim 10 , wherein the amount of recombinant von Willebrand factor is greater than 2000 RCoU/kg.12. The method of claim 11 , wherein the amount of recombinant von Willebrand factor is greater than 4000 RCoU/kg.13. A method of testing an agent for its ability to reduce blood clotting in a mammal administered recombinant von Willebrand factor in an amount effective to cause a pathology comprising comparing the pathology in an animal model in the presence and absence of a test agent wherein decreased incidence or severity of the pathology in the presence of the test agent indicates that the test agent has the ability to reduce blood clotting.14. The method of further comprising administering the ...

NON-HUMAN ANIMALS HAVING A HUMANIZED SIGNAL-REGULATORY PROTEIN GENE

Genetically modified non-human animals and methods and compositions for making and using the same are provided, wherein the genetic modification comprises a humanization of an endogenous signal-regulatory protein gene, in particular a humanization of a SIRPα gene. Genetically modified mice are described, including mice that express a human or humanized SIRPα protein from an endogenous SIRPα locus. 153.-. (canceled)54. A method of making a rat , comprising (i) comprises exon 1 of a rat SIRPα gene, exons 2, 3 and 4 of a human SIRPα gene, and exons 5, 6, 7 and 8 of the rat SIRPα gene,', '(ii) is operably linked to a rat SIRPα promoter at the endogenous rat SIRPα locus, and', '(iii) encodes a humanized SIRPα protein comprising an extracellular portion of the human SIRPα protein encoded by the human SIRPα gene and an intracellular portion of the rat SIRPα protein encoded by the rat SIRPα gene;, 'a) modifying an endogenous rat SIRPα locus in a rat ES cell such that the modified SIRPα locus comprises a humanized SIRPα gene, wherein the humanized SIRPα gene'}b) obtaining a rat ES cell comprising the modified SIRPα locus; andc) generating a rat using the rat ES cell of step (b), wherein the rat generated is homozygous for the humanized SIRPα gene.55. The method of claim 54 , wherein the extracellular portion of the human SIRPα protein comprises amino acid residues 28-362 of the human SIRPα protein.56. The method of claim 54 , wherein the human SIRPα protein comprises the amino acid sequence as set forth in SEQ ID NO: 4.57. The method of claim 54 , wherein the rodent does not express an endogenous rodent SIRPα protein.58. A method of engrafting human cells into a rat claim 54 , comprising the steps of: (i) comprises exon 1 of a rat SIRPα gene, exons 2, 3 and 4 of a human SIRPα gene, and exons 5, 6, 7 and 8 of the rat SIRPα gene,', '(ii) is operably linked to a rat SIRPα promoter at the endogenous rat SIRPα locus, and', 'wherein the rat is homozygous for the humanized SIRPα ...

T CELL REGULATION

Combinations of anti-cancer antibodies and inhibitory antibodies to CD223 overcome immune suppression in cancer patients. The inhibitory antibodies may be generated in an animal by injection of fragments of CD223. Antibodies may be monoclonal antibodies or single chain antibodies or humanized antibodies. 1. A method for treating a mammal with a cancer , comprising:administering to the mammal a first antibody which specifically binds to CD223 protein and inhibits negative T cell regulatory function of CD223; andadministering to the mammal a second antibody which is an anti-cancer antibody.2. The method of wherein the mammal is a human cancer patient.3. The method of wherein the first antibody is a monoclonal antibody.4. The method of wherein an amount of the first antibody is administered sufficient to increase the number of T cells in the mammal.5. The method of wherein an amount of the first antibody is administered sufficient to enhance an immune T cell response to the cancer. The United States government, National Institutes of Health, provided funding (AI39480) for work that underlies the invention. Under the terms of that funding agreement, the United States government retains certain rights in the invention.The invention relates to therapeutic and drug screening methods.A variety of diseases are characterized by the development of progressive immunosuppression in a patient. The presence of an impaired immune response in patients with malignancies has been particularly well documented. Cancer patients and tumor-bearing mice have been shown to have a variety of altered immune functions such as a decrease in delayed type hypersensitivity, a decrease in lytic function and proliferative response of lymphocytes. S. Broder et al., N. Engl. J. Ned., 299: 1281 (1978); E. M. Hersh et al., N. Engl. J. Med., 273: 1006 (1965); North and Burnauker, (1984). Many other diseases or interventions are also characterized by the development of an impaired immune response. For ...

Screening method for selected amino lipid-containing compositions

The invention features a method of identifying therapeutically relevant compositions which include a therapeutic agent and 2,2-Dilinoley 1-4-dimethylaminomethyl-[1,3]-dioxolane by screening for an effect of the agent on the liver of a model subject.

Mammalian gene modification method using electroporation

An object is to develop a technology enabling utilization, by only an extremely simple technique, of a technology which is widely applicable to mammals without requiring the utilization of an ES cell, and which involves modifying a certain gene by targeting a certain sequence on a genome (genome editing technology based on ZFN or the like). Provided is a technology for efficiently modifying an arbitrary target gene of a mammal, by immersing a pronuclear stage mammalian zygote with an intact zona pellucida into a solution containing a pair of molecules of mRNA having a certain sequence, and performing electroporation treatment through application of multiple square-wave pulses in three steps with the total electric energy of a first electric pulse adjusted within a predetermined range.

HUMAN LAMBDA LIGHT CHAIN MICE

Genetically modified mice are provided that express human λ variable (hVλ) sequences, including mice that express hVλ sequences from an endogenous mouse λ light chain locus, mice that express hVλ sequences from an endogenous mouse κ light chain locus, and mice that express hVλ sequences from a transgene or an episome wherein the hVλ sequence is linked to a mouse constant sequence. Mice are provided that are a source of somatically mutated human λ variable sequences useful for making antigen-binding proteins. Compositions and methods for making antigen-binding proteins that comprise human λ variable sequences, including human antibodies, are provided. 120-. (canceled)21. A method of making an antibody comprising a human light chain variable domain , the method comprising: (i) one or more unrearranged human Vλ gene segments,', '(ii) one or more unrearranged human Jλ gene segments, and', '(iii) one or more human Cλ gene segments,', 'wherein the one or more unrearranged human Vλ gene segments of (i) and the one or more unrearranged human Jλ gene segments of (ii) are at an endogenous mouse λ light chain locus;, '(a) exposing a genetically modified mouse to an antigen, wherein the genetically modified mouse has a genome that comprises(b) allowing the genetically modified mouse to develop an immune response to the antigen; and(c) isolating from the mouse of (b) an antibody specific to the antigen, wherein the antibody comprises a human light chain variable domain expressed from a rearranged human lambda light chain variable region derived from a human Vλ gene segment of the one or more unrearranged human Vλ gene segments of (i) and a human Jλ gene segment of the one or more unrearranged human Jλ gene segments of (ii).22. The method of claim 21 , wherein the genome of the genetically modified mouse includes an endogenous lambda light chain variable region sequence.23. The method of claim 21 , wherein the endogenous mouse λ light chain locus comprises one or more mouse Cλ ...

Screening method for selected amino-lipid-containing compositions

The invention features a method of identifying therapeutically relevant compositions which include a therapeutic agent and 2,2-dimethylaminomethyl-[1-3]-dioxolane by screening for an effect of the agent on the liver of a model subject.

Targeted modification of rat genome

Compositions and methods are provided for modifying a rat genomic locus of interest using a large targeting vector (LTVEC) comprising various endogenous or exogenous nucleic acid sequences as described herein. Compositions and methods for generating a genetically modified rat comprising one or more targeted genetic modifications in their germline are also provided. Compositions and methods are provided which comprise a genetically modified rat or rat cell comprising a targeted genetic modification in the rat interleukin-2 receptor gamma locus, the rat ApoE locus, the rat Rag2 locus, the rat Rag1 locus and/or the rat Rag2/Rag1 locus. The various methods and compositions provided herein allows for these modified loci to be transmitted through the germline.

Non-human animals having a disruption in a c9orf72 locus

A non-human animal model for neurodegenerative and/or inflammatory diseases is provided, which non-human animal comprises a disruption in a C9ORF72 locus. In particular, non-human animals described herein comprise a deletion of an entire coding sequence of a C9ORF72 locus. Methods of identifying therapeutic candidates that may be used to prevent, delay or treat one or more neurodegenerative (e.g., amyotrophic lateral sclerosis (ALS, also referred to as Lou Gehrig's disease) and frontotemporal dementia (FTD)), autoimmune and/or inflammatory diseases (e.g., SLE, glomerulonephritis) are also provided.

NON-HUMAN ANIMALS HAVING A HUMANIZED SIGNAL-REGULATORY PROTEIN GENE

Genetically modified non-human animals and methods and compositions for making and using the same are provided, wherein the genetic modification comprises a humanization of an endogenous signal-regulatory protein gene, in particular a humanization of a SIRPα gene. Genetically modified mice are described, including mice that express a human or humanized SIRPα protein from an endogenous SIRPα locus. 1. A mouse expressing a SIRPα polypeptide comprising an extracellular portion of a human SIRPα protein and an intracellular portion of a mouse SIRPα protein.2. The mouse of claim 1 , wherein the extracellular portion of a human SIRPα protein comprises amino acids corresponding to residues 28-362 of a human SIRPα protein that appears in Table 3.3. The mouse of or claim 1 , wherein the extracellular portion of a human SIRPα protein shares a percent identity of at least 50% with a corresponding extracellular portion of a human SIRPα protein that appears in Table 3.4. The mouse of or claim 1 , wherein the shared percent identity is at least 60% with a corresponding extracellular portion of a human SIRPα protein that appears in Table 3.5. The mouse of or claim 1 , wherein the shared percent identity is at least 70% with a corresponding extracellular portion of a human SIRPα protein that appears in Table 3.6. The mouse of or claim 1 , wherein the shared percent identity is at least 80% with a corresponding extracellular portion of a human SIRPα protein that appears in Table 3.7. The mouse of or claim 1 , wherein the extracellular portion of a human SIRPα protein has a sequence that is at least 90% identical to an extracellular portion of a human SIRPα protein that appears in Table 3.8. The mouse of or claim 1 , wherein the extracellular portion of a human SIRPα protein has a sequence that is at least 95% identical to an extracellular portion of a human SIRPα protein that appears in Table 3.9. The mouse of or claim 1 , wherein the extracellular portion of a human SIRPα protein ...

TELOMERASE REVERSE TRANSCRIPTASE-BASED THERAPIES

The invention provides compositions and methods useful for the treatment and prevention of conditions associated with short telomere length. 112.-. (canceled)13. A method of treating a condition associated with a disease , the method comprising:administering a recombinant viral vector comprising at least a capsid and a nucleic acid comprising a coding sequence for telomerase reverse transcriptase (TERT) to a subject, wherein the condition is associated with pulmonary fibrosis.14. The method of claim 13 , wherein TERT is encoded by a nucleic acid sequence comprising a sequence that is at least 60% identical to the sequence of SEQ ID NO: 1 or SEQ ID NO: 3.15. The method of claim 13 , wherein TERT comprises an amino acid sequence that is at least 60% identical to the amino acid sequence of SEQ ID NO:2 or SEQ ID NO: 4.16. The method of claim 13 , wherein the nucleic acid sequence encoding TERT is operably linked to a regulatory sequence that drives the expression of the coding sequence.17. The method of claim 13 , wherein the vector is a non-integrative vector.18. The method of claim 13 , wherein the vector is an adeno-associated virus-based non-integrative vector.19. The method of claim 13 , wherein the vector is an adeno-associated virus-based vector whose capsid is derived from a serotype 9 adeno-associated virus (AAV9).20. The method of claim 19 , wherein the nucleic acid sequence packaged in the capsid is flanked at both ends by internal terminal repeats of the serotype 2 adeno-associated virus.21. The method of claim 13 , wherein the vector comprises a regulatory sequence which is a constitutive promoter.22. The method of claim 21 , wherein the constitutive promoter is the cytomegalovirus (CMV) promoter.23. The method of claim 13 , wherein the pulmonary fibrosis is characterized by mutations in a gene or genes involved in telomere maintenance. This invention falls within the field of molecular biology, biotechnology and medicine. More particularly, it relates to ...

SCREENING METHOD FOR SELECTED AMINO-LIPID-CONTAINING COMPOSITIONS

The invention features a method of identifying therapeutically relevant compositions which include a therapeutic agent and 2,2-dimethylaminomethyl-[1-3]-dioxolane by screening for an effect of the agent on the liver of a model subject. 1. A method of evaluating a composition that includes a therapeutic agent and 2 ,2-Dilinoley 1-4-dimethylaminomethyl-[1 ,3]-dioxolane comprising:providing a composition that includes a therapeutic agent and 2,2-Dilinoley 1-4-dimethylaminomethyl-[1,3]-dioxolane;administering the composition to a test animal; anddetermining the effect of the composition on the expression of a target gene expressed in the liver of the animal,thereby evaluating the composition.2. The method of claim 1 , wherein the therapeutic agent is an RNA-based construct.3. The method of claim 2 , wherein the RNA-based construct is a dsRNA.4. The method of claim 1 , wherein the target gene is Factor VII.5. The method of claim 1 , wherein determining the effect of the composition comprises determining target protein levels.6. The method of claim 1 , wherein determining the effect of the composition comprises determining target mRNA levels.7. The method of claim 5 , wherein the level of target protein in blood is determined.8. The method of claim 6 , wherein the level of target mRNA in liver is determined.9. The method of claim 1 , further comprising comparing expression of the target gene with a preselected reference value.10. The method of claim 1 , wherein the composition further comprises a third component.11. The method of claim 1 , wherein the therapeutic agent is an antisense RNA claim 1 , ribozyme or microRNA.12. The method of claim 1 , wherein the test animal is a rodent.13. The method of claim 1 , wherein the test animal is a mouse.14. The method of claim 1 , wherein the composition reduces FVII protein or mRNA levels in the blood.15. The method of claim 1 , wherein the composition reduces FVII protein or mRNA levels in the liver.16. The method of claim 1 , ...

Delivery methods and compositions for nuclease-mediated genome engineering

Disclosed herein are methods and compositions for delivery of engineered nucleases and donor molecules into the genome of a cell.

High activity regulatory elements

Provided herein are compositions and methods for driving high expression of a transgene. Compositions and methods for driving high expression of a transgene comprising one or more human-derived regulatory elements, which, when operably linked to a transgene, can result in high expression of the transgene in one or more cell types or tissues.

HUMAN ARTIFICIAL CHROMOSOME CONTAINING HUMAN ANTIBODY LAMBDA LIGHT CHAIN GENE AND NON-HUMAN ANIMAL CONTAINING THE HUMAN ARTIFICIAL CHROMOSOME CAPABLE OF GENETIC TRANSMISSION

The present invention relates to a human artificial chromosome which is genetically transmissible to the next generation with high efficiency and the method for using the same. More specifically, the present invention relates to: a human artificial chromosome in which an about 3.5 Mb to about 1 Mb region containing an antibody λ light chain gene derived from human chromosome 22 is bound to a chromosome fragment which is transmissible to a progeny through a germ line of a non-human animal, said chromosome fragment is derived from another human chromosome; a non-human animal carrying the human artificial chromosome and an offspring thereof; a method for producing the non-human animal; a method for producing a human antibody using the nonhuman animal or an offspring thereof; and a human antibody-producing mouse carrying the human artificial chromosome. 1. A human antibody-producing mouse , wherein an unrearranged human antibody heavy chain locus , an unrearranged human antibody κ light chain locus , and an unrearranged human antibody λ light chain locus are carried , at least both alleles of endogenous antibody heavy chain and κ light chain are disrupted or inactivated , and a human antibody heavy chain comprising a human antibody Ig γ isotype , a human antibody κ light chain , and a human antibody λ light chain are expressed in serum.218.-. (canceled) This application is a continuation of U.S. patent application Ser. No. 15/298,037 (Allowed), filed on Oct. 19, 2016, which is a divisional of U.S. Pat. No. 9,499,838, issued on Nov. 22, 2016, which is a continuation of U.S. Pat. No. 7,402,729, issued on Jul. 22, 2008, which is a divisional of U.S. Pat. No. 7,476,536, issued on Jan. 13, 2009 which is the National Stage Entry of PCT/JP2002/004587, filed on May 10, 2002. The contents of the aforementioned applications are hereby incorporated by reference.The instant application contains a Sequence Listing which has been submitted via EFS-Web and is hereby incorporated by ...

NON-HUMAN ANIMALS HAVING A HUMANIZED CLUSTER OF DIFFERENTIATION 47 GENE

Non-human animals, and methods and compositions for making and using the same, are provided, wherein said non-human animals comprise a humanization of an endogenous cluster of differentiation (CD) gene, in particular a humanization of a CD47 gene. Said non-human animals may be described, in some embodiments, as having a genetic modification to an endogenous CD47 gene so that said non-human animals express a CD47 polypeptide that includes a human portion and a non-human portion (e.g., a murine portion). 1108.-. (canceled)109. A genetically modified mouse whose genome comprises a replacement of a genomic fragment comprising exons 2-7 of a mouse CD47 gene at an endogenous mouse CD47 locus with a human genomic fragment comprising exons 2-7 of a human CD47 gene to form a humanized CD47 gene ,wherein the exons of the humanized CD47 gene consist of exon 1 of the mouse CD47 gene, exons 2-7 of the human CD47 gene, and the remaining exons downstream of exon 7 of the mouse CD47 gene,wherein the humanized CD47 gene is under control of the endogenous mouse CD47 promoter at the endogenous mouse CD47 locus, andwherein the mouse expresses a humanized CD47 protein encoded by the humanized CD47 gene.110. The genetically modified mouse of claim 109 , whose genome further comprises a replacement of a genomic fragment comprising exons 2 claim 109 , 3 and 4 of a mouse SIRPα gene at an endogenous mouse SIRPα locus with a genomic fragment comprising exons 2 claim 109 , 3 and 4 of a human SIRPα gene to form a humanized SIRPα gene claim 109 , wherein the humanized SIRPα gene is operably linked to the endogenous mouse SIRPα promoter at the endogenous mouse SIRPα locus claim 109 , and wherein the humanized SIRPα gene encodes a humanized SIRPα protein comprising an extracellular portion of the human SIRPα protein encoded by the human SIRPα gene and an intracellular portion of the endogenous mouse SIRPα protein encoded by the mouse SIRPα gene.111. The genetically modified mouse of claim 110 , ...

HUMAN LAMBDA LIGHT CHAIN MICE

Genetically modified mice are provided that express human λ variable (hVλ) sequences, including mice that express hVλ sequences from an endogenous mouse λ light chain locus, mice that express hVλ sequences from an endogenous mouse κ light chain locus, and mice that express hVλ sequences from a transgene or an episome wherein the hVλ sequence is linked to a mouse constant sequence. Mice are provided that are a source of somatically mutated human λ variable sequences useful for making antigen-binding proteins. Compositions and methods for making antigen-binding proteins that comprise human λ variable sequences, including human antibodies, are provided. 120-. (canceled)21. A method of generating a human λ light chain variable region , the method comprising:(a) immunizing a genetically modified mouse with an antigen, wherein the germline genome of the genetically modified mouse comprises:one or more human Vλ gene segments and one or more human Jλ gene segments, wherein the one or more human Vλ gene segments and the one or more human Jλ gene segments replace endogenous mouse Vκ gene segments and endogenous Jκ gene segments; andwherein the one or more human Vλ gene segments and one or more human Jλ gene segments are operably linked to an endogenous mouse κ light chain constant (Cκ) region gene; and(b) determining a human λ light chain variable region that encodes a human λ light chain variable domain of an antibody that specifically binds the antigen and was generated by the genetically modified mouse, wherein the human λ light chain variable region is derived from a human Vλ gene segment of the one or more human Vλ gene segments and a human Jλ gene segment of the one or more human Jλ gene segments.22. The method of claim 21 , comprising isolating a B cell of the genetically modified mouse and amplifying the λ light chain variable region from the B cell of the genetically modified mouse.23. The method of claim 21 , wherein the one or more human Vλ gene segments and the ...

MOUSE LYMPHOMA CELL LINE AND ANIMAL MODEL OF HUMAN HIGH GRADE B-CELL LYMPHOMA

The invention relates to a new, spontaneous mouse lymphoma cell line displaying CD19, B220, MHC II, surface IgG2a/kappa chain and MAC-1, which is negative for CD5, animal models of B-cell lymphoma based on said cell line and methods for assessing lymphoma propagation and lymphoma expansion based on said cell line. 1. A population of cells of the mouse lymphoma cell line deposited at the Deutsche Sammlung von Mikroorganismen and Zellkulturen (DSMZ) on Sep. 24 , 2015 under the number DSMZ ACC3278 or a population of cells derived therefrom , wherein said cells are positive for CD19 , B220 , MHC II , surface IgG2a/kappa chain and MAC-1 , and negative for CD5.2. The population of cells according to wherein said cells comprise a chromosomal translocation selected from the group consisting of the following translocations: t(10:6) claim 1 , t(6:10) claim 1 , t(11:19) and t(10:11).3. The population of cells according to claim 1 , wherein said population of cells claim 1 , when administered intraperitoneally to a mouse in a dose of 10to 5×10cells/recipient claim 1 , preferably 10to 5×10cells/recipient claim 1 , expands to one or more site(s) selected from the omentum and the fat associated lymphoid clusters (FALC) along the blood vessels in the mesentery as primary site of expansion within 7 days after administration.4. The population of cells according to claim 3 , wherein said population of cells claim 3 , upon said administration claim 3 , expands to said expansion site(s) within 5 days claim 3 , preferably within approximately 3 days.5. The population of cells according to claim 1 , wherein said population of cells claim 1 , when administered intraperitoneally to a mouse in a dose of 10to 5×10cells/recipient claim 1 , preferably 10to 5×10cells/recipient claim 1 , are substantially absent from a tissue or organ selected from: spleen claim 1 , peripheral lymph nodes and liver up to 8 days after intraperitoneal administration to a mouse.6. The population of cells according ...

NON-HUMAN ANIMALS HAVING A HUMANIZED B-CELL ACTIVATING FACTOR GENE

Non-human animals, cells, methods and compositions for making and using the same are provided, wherein the non-human animals and cells comprise a humanized B-cell activating factor gene. Non-human animals and cells that express a human or humanized B-cell activating factor protein from an endogenous B-cell activating factor locus are described. 121.-. (canceled)22. An isolated mouse cell or tissue whose genome comprisesa replacement of a mouse genomic fragment comprising exons 3-6 of an endogenous mouse B-cell Activating Factor (Baff) gene at an endogenous mouse Baff locus in the mouse ES cell, with a human genomic fragment comprising exons 3-6 of a human BAFF gene to form a humanized Baff gene,wherein the coding exons of the humanized Baff gene consist of exons 1-2 of the endogenous mouse Baff gene and exons 3-6 of the human BAFF gene,wherein the humanized Baff gene is under control of the mouse Baff promoter at the endogenous mouse Baff locus and encodes a humanized Baff protein comprising an extracellular portion of the human BAFF protein linked to an intracellular portion of the mouse Baff protein encoded by the endogenous mouse Baff gene,wherein the extracellular portion of the human BAFF protein is at least 98% identical to the amino acid sequence as set forth in amino acids 142 to 285 of SEQ ID NO: 5, andwherein the mouse cell or tissue expresses thed humanized Baff protein.23. The mouse cell or tissue of claim 22 , wherein the extracellular portion of the human BAFF protein consists of amino acids 142 to 285 of SEQ ID NO: 5.24. The mouse cell or tissue of claim 22 , wherein the humanized Baff protein consists of the amino acid sequence as set forth in SEQ ID NO: 7.25. A cell or tissue isolated from a mouse claim 22 , wherein the mouse genome comprisesa replacement of a mouse genomic fragment comprising exons 3-6 of an endogenous mouse B-cell Activating Factor (Baff) gene at an endogenous mouse Baff locus in the mouse ES cell, with a human genomic fragment ...

Compositions and Methods for Increasing Red Blood Cells

The invention relates generally to a composition and method for increasing the frequency, amount, or presence of red blood cells in peripheral blood. In one embodiment, the invention comprises the inhibition of, or genetic modification of the genes encoding, one or more scavenger receptors. In one aspect, the invention relates to treatments of anemia. 1. A composition for increasing red blood cells (RBCs) in peripheral blood comprising an inhibitor of one or more scavenger receptors.2. The composition of claim 1 , wherein the inhibitor is an inhibitor of scavenger receptor B1.3. The composition of claim 1 , wherein the inhibitor is selected from the group consisting of a nucleic acid claim 1 , a siRNA claim 1 , an antisense nucleic acid claim 1 , a ribozyme claim 1 , a peptide claim 1 , a small molecule claim 1 , an antagonist claim 1 , an aptamer claim 1 , and a peptidomimetic.4. The composition of claim 1 , wherein the inhibitor is selected from the group consisting of D-4F claim 1 , BLT-1 claim 1 , and ITX-5061.5. (canceled)6. The composition of claim 1 , wherein the composition reduces at least one selected from the group consisting of: the destruction of red blood cells and the sequestration of red blood cells.7. (canceled)8. A method for treating a subject in need thereof claim 1 , the method comprising administering to the subject an effective amount of a composition comprising an inhibitor of one or more scavenger receptors claim 1 , wherein the subject has or is at risk for developing at least one selected from the group consisting of: anemia and a cholesterol abnormality.9. The method of claim 8 , wherein the inhibitor is an inhibitor of scavenger receptor B1.10. The method of claim 8 , wherein the inhibitor is selected from the group consisting of a nucleic acid claim 8 , a siRNA claim 8 , an antisense nucleic acid claim 8 , a ribozyme claim 8 , a peptide claim 8 , a small molecule claim 8 , an antagonist claim 8 , an aptamer claim 8 , and a ...

Genetically Modified Mice and Engraftment

A mouse with a humanization of the miL-3 gene and the mGM-CSF gene, a knockout of a mRAG gene, and a knockout of a mII2rg subunit gene; and optionally a humanization of the TPO gene is described. A RAG/II2rg KO/hTPO knock-in mouse is described. A mouse engrafted with human hematopoietic stem cells (HSCs) that maintains a human immune cell (HIC) population derived from the HSCs and that is infectable by a human pathogen, e.g., S. typhi or M. tuberculosis is described. A mouse that models a human pathogen infection that is poorly modeled in mice is described, e.g., a mouse that models a human mycobacterial infection, wherein the mouse develops one or more granulomas comprising human immune cells. A mouse that comprises a human hematopoietic malignancy that originates from an early human hematopoietic cells is described, e.g., a myeloid leukemia or a myeloproliferative neoplasia.

Mice with Modified Glucose-6-Phosphate Dehydrogenase (G6PD) and Uses Thereof

Provided is a transgenic mouse with modified glucose-6-phosphate dehydrogenase which can be used as a model and screening tool for various aspects of glucose-6-phosphate dehydrogenase deficiency.

USE OF MAPK INHIBITORS TO REDUCE LOSS OF HEMATOPOIETIC STEM CELLS DURING EX VIVO CULTURE AND/OR GENETIC MANIPULATION

Provided herein are methods for preparing hematopoietic stem cells (HSCs), for example, human HSCs suitable for engraftment in the presence of a p38 MAPK inhibitor. Methods for assessing engraftment of HSCs (e.g., human HSCs) are also provided. 1. A method for preparing hematopoietic stem cells (HSCs) having enhanced engraftment activity , the method comprising:(i) providing HSCs, which have undergone a genetic manipulation that induces a DNA double strand break; and(ii) culturing the HSCs in a medium that comprises an effective amount of a p38 mitogen-activated protein kinase (MAPK) inhibitor.2. The method of claim 1 , wherein the HSCs are resting HSCs.3. The method of claim 1 , wherein the genetic manipulation comprises transduction of an integrating vector.4. The method of claim 1 , wherein the genetic manipulation comprise genome editing.5. The method of claim 1 , wherein the MAPK inhibitor is doramapimod claim 1 , ralimetinib claim 1 , an aminopyridine-based claim 1 , ATP-competitive inhibitor of p38 MAPK claim 1 , or a pyridinyl imidazole inhibitor.6. The method of claim 1 , wherein the HSCs are obtained from a subject.7. The method of claim 6 , wherein the subject is a human subject.8. The method of claim 7 , wherein the HSCs are adult HSCs obtained from the bone marrow or peripheral blood cells of the human subject.9. The method of claim 7 , wherein the HSCs are obtained from umbilical cord blood cells of the human subject.10. The method of claim 3 , wherein the integrating vector is a viral vector.11. The method of claim 10 , wherein the viral vector is a retroviral vector or a lentiviral vector.12. The method of claim 1 , further comprising (iii) administering the HSCs obtained from step (ii) to a subject in need thereof.13. The method of claim 12 , wherein the subject is the same subject from whom the HSCs are obtained.14. The method of claim 1 , wherein step (ii) is performed for 1 to 7 days.15. A method for preparing human hematopoietic stem cells (HSCs ...

Targeted modification of rat genome

Compositions and methods are provided for modifying a rat genomic locus of interest using a large targeting vector (LTVEC) comprising various endogenous or exogenous nucleic acid sequences as described herein. Compositions and methods for generating a genetically modified rat comprising one or more targeted genetic modifications in their germline are also provided. Compositions and methods are provided which comprise a genetically modified rat or rat cell comprising a targeted genetic modification in the rat interleukin-2 receptor gamma locus, the rat ApoE locus, the rat Rag2 locus, the rat Rag1 locus and/or the rat Rag2/Rag1 locus. The various methods and compositions provided herein allows for these modified loci to be transmitted through the germline.

MRGPRX2/MRGPRB2 EXPRESSING CELL BASED ASSAY TO DETECT PSEUDO-ALLERGIC DRUG REACTIONS AND TO IDENTIFY BLOCKERS TO PREVENT THE ADVERSE REACTIONS

The present invention relates to cells and methods for detecting compounds that induce a pseudo-allergic-type reaction and methods for reducing the severity of a pseudo-allergic-type reaction. 122-. (canceled)23. A method for identifying an antagonist of MrgprX2 or MrgprB2 comprising:contacting an isolated cell comprising a recombinant nucleic acid that expresses mas-related G-protein coupled receptor member X2 (MrgprX2) or MrgprB2 with a compound that induces a pseudo-allergic-type reaction,contacting the isolated cell with a candidate antagonist,detecting activation of MrgprX2 or MrgprB2, wherein a decrease in activation of MrgprX2 or MrgprB2 relative to the activation of MrgprX2 or MrgprB2 in the absence of the compound determines that the candidate compound is an antagonist.24. The method of claim 23 , wherein the recombinant nucleic acid expresses MrgprX2.25. The method of claim 23 , wherein the recombinant nucleic acid expresses MrgprB2.26. The method of claim 24 , wherein the recombinant nucleic acid that expresses MrgprX2 comprises one or more mutations.27. The method of claim 26 , wherein the one or more mutations produces an MrgprX2 protein incapable of activating a signal transduction pathway.28. The method of claim 25 , wherein the recombinant nucleic acid that expresses MrgprB2 comprises one or more mutations.29. The method of claim 28 , wherein the one or more mutations produces an MrgprB2 protein incapable of activating a signal transduction pathway.30. The method of claim 23 , wherein the isolated cell comprises a human embryonic kidney 293 (HEK 293) cell.31. The method of wherein the MrgprB2 comprises the amino acid sequence of SEQ ID NO: 3.32. The method of wherein the MrgprX2 comprises the amino acid sequence of SEQ ID NO: 1. This application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No: 62/032,350, filed Aug. 1, 2014, which is incorporated herein by reference in its entirety.The present invention ...

Human antibodies derived from immunized xenomice

Antibodies with fully human variable regions against a specific antigen can be prepared by administering the antigen to a transgenic animal which has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled. Various subsequent manipulations can be performed to obtain either antibodies per se or analogs thereof.

Generation of xenogeneic antibodies

The subject invention provides non-human mammalian hosts characterized by inactivated endogenous Ig loci and functional human Ig loci for response to an immunogen to produce human antibodies or analogs thereof. The hosts are produced by repetitive transformations of embryonic stem cells by homologous recombination, preferably in conjunction with breeding. Different strategies are employed for recombination of the human loci randomly or at analogous host loci.

Generation of xenogeneic antibodies

The subject invention provides non-human mammalian hosts characterized by inactivated endogenous Ig loci and functional human Ig loci for response to an immunogen to produce human antibodies or analogs thereof. The hosts are produced by repetitive transformations of embryonic stem cells by homologous recombination, preferably in conjunction with breeding. Different strategies are employed for recombination of the human loci randomly or at analogous host loci.

Genetically Modified Non-Human Animals and Methods of Use Thereof

The invention relates generally to genetically modified non-human animals expressing human polypeptides and their methods of use,

Transgenic non-human animals capable of producing heterologous antibodies of various isotypes

The invention relates to transgenic non-human animals capable of producing heterologous antibodies and transgenic non-human animals having inactivated endogenous immunoglobulin genes. In one aspect of the invention, endogenous immunoglobulin genes are suppressed by antisense polynucleotides and/or by antiserum directed against endogenous immunoglobulins. Heterologous antibodies are encoded by immunoglobulin genes not normally found in the genome of that species of non-human animal. In one aspect of the invention, one or more transgenes containing sequences of unrearranged heterologous human immunoglobulin heavy chains are introduced into a non-human animal thereby forming a transgenic animal capable of functionally rearranging transgenic immunoglobulin sequences and producing a repertoire of antibodies of various isotypes encoded by human immunoglobulin genes. Such heterologous human antibodies are produced in B-cells which are thereafter immortalized, e.g., by fusing with an immortalizing cell line such as a myeloma or by manipulating such B-cells by other techniques to perpetuate a cell line capable of producing a monoclonal heterologous antibody. The invention also relates to heavy and light chain immunoglobulin transgenes for making such transgenic non-human animals as well as methods and vectors for disrupting endogenous immunoglobulin loci in the transgenic animal.

GENERATION OF XENOGENIC ANTIBODIES

Transgenic non-human animals capable of producing heterologous antibodies

The invention relates to transgenic non-human animals capable of producing heterologous antibodies and transgenic non-human animals having inactivated endogenous immunoglobulin genes. In one aspect of the invention, endogenous immunoglobulin genes are suppresed by antisense polynucleotides and/or by antiserum directed against endogenous immunoglobulins. Heterologous antibodies are encoded by immunoglobulin genes not normally found in the genome of that species of non-human animal. In one aspect of the invention, one or more transgenes containing sequences of unrearranged heterogolous human immunoglobulin heavy chains are introduced into a non-human animal thereby forming a transgenic animal capable of functionally rearranging transgenic immunoglobulin sequences and producing a repertoire of antibodies of various isotypes encoded by human immunoglobulin genes. Such heterologous human antibodies are produced in B-cells which are thereafter immortalized, e.g., by fusing with an immortalizing cell line such as a myeloma or by manipulating such B-cells by other techniques to perpetuate a cell line capable of producing a monoclonal heterologous antibody. The invention also relates to heavy and light chain immunoglobulin transgenes for making such transgenic non-human animals as well as methods and vectors for disrupting endogenous immunoglobulin loci in the transgenic animal.

Murine expression of human ig\ locus

含人抗体λ轻链基因的人类人工染色体

一种可高效转移至后代(下一代)的人类人工染色体及其使用方法。即这样一种人类人工染色体：其中含人第22号染色体来源的抗体λ轻链基因的约3.5Mb至约1Mb区域连接至另一个人类染色体来源的染色体片段，其可通过非人动物生殖系统传递至后代；具有该人工人类染色体的的非人动物及其后代；构建所述非人动物的方法；使用所述非人动物或其后代构建人抗体的方法；以及具有上述人类人工染色体的生产人抗体的小鼠。

Lymphoides cd30-antigen (ki-1), dessen protein- und die zugehoerige nucleotidsequenz, seine herstellung sowie mittel zur diagnose und untersuchung von tumoren

ARTIFICIAL HUMAN CHROMOSOME CONTAINING HUMAN ANTIBODY μ LIGHT CHAIN GENE

Transgenic mice depleted in a mature lymphocytic cell-type

Transgenic mice having a phenotype characterized by the substantial depletion of a mature lymphocytic cell type otherwise naturally occurring in the species from which the transgenic mouse is derived. The phenotype is conferred in the transgenic mouse by a transgene contained in at least the precursor stem cell of the lymphocytic cell type which is depleted. The transgene comprised is a DNA sequence encoding a lymphatic polypeptide variant which inhibits maturation of the lymphocytic cell type.

Human antibodies derived from immunized xenomice

Antibodies with fully human variable regions against a specific antigen can be prepared by administering the antigen to a transgenic animal which has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled. Various subsequent manipulations can be performed to obtain either antibodies per se or analogs thereof.

Transgenic non-human animals depleted in a mature lymphocytic cell-type

Transgenic mice having a phenotype characterized by the substantial depletion of a mature lymphocytic cell type otherwise naturally occurring in the species from which the transgenic mouse is derived. The phenotype is conferred in the transgenic mouse by a transgene contained in at least the precursor stem cell of the lymphocytic cell type which is depleted. The transgene comprised is a DNA sequence encoding a lymphatic polypeptide variant which inhibits maturation of the lymphocytic cell type.

T-세포가 결핍된 유전자 이식 마우스

본 발명은 T-세포가 결핍된 유전자 이식 마우스에 관한 것으로 H2K 프로모터에 인간 열충격 단백질(Hsp)의 유전자가 융합된 유전자를 마우스에 이식하므로서 제공된다. 흉선이 위축되고 성숙 T-세포가 검출되지 않는 T-세포가 결핍된 유전자 이식 마우스주(transgenic mice line)를 얻을 수 있었으며, 이는 자가면역질환 발생 기전의 규명 및 면역 억제제의 개발, 새로운 약의 검정 시스템 등의 연구분야에서 유용하게 이용될 수 있다.

Application of propagated populations of hematopoietic stem cells/progenitor cells

FIELD: biotechnology. SUBSTANCE: present invention relates to the field of biotechnology and discloses new methods and applications of a clinical product of umbilical cord blood, including CD34 + enriched and propagated stem cells. This umbilical cord blood product is used to induce immunological tolerance in the transplant recipient, reduce the acute ‘graft versus host’ reaction, reduce the rejection of allogeneic tissue in the transplant recipient, and improve the outcome of transplantation in the transplant recipient. EFFECT: present invention makes it possible to expand the arsenal of tools for improving the outcome of transplantation. 18 cl, 3 ex, 13 dwg РОССИЙСКАЯ ФЕДЕРАЦИЯ (19) RU (11) (13) 2 747 728 C2 (51) МПК A61K 35/14 (2015.01) A61K 35/28 (2015.01) A61K 35/51 (2015.01) ФЕДЕРАЛЬНАЯ СЛУЖБА ПО ИНТЕЛЛЕКТУАЛЬНОЙ СОБСТВЕННОСТИ (12) ОПИСАНИЕ ИЗОБРЕТЕНИЯ К ПАТЕНТУ (52) СПК A61K 35/51 (2021.02); A61K 35/14 (2021.02); A61K 35/28 (2021.02) (21)(22) Заявка: 2018124303, 05.12.2016 (24) Дата начала отсчета срока действия патента: (73) Патентообладатель(и): ФРЕД ХАТЧИНСОН КЭНСЕР РИСЕРЧ СЕНТЕР (US) Дата регистрации: 13.05.2021 04.12.2015 US 62/263,470; 04.12.2015 US 62/263,573 (43) Дата публикации заявки: 13.01.2020 Бюл. № 2 (45) Опубликовано: 13.05.2021 Бюл. № 14 (56) Список документов, цитированных в отчете о поиске: US 7270810 B2, 18.09.2007. KLAUS J. et al., High CD34+ cell dose is a significant factor for hematologic reconstitution of patients with multiple myeloma (MM) or AL-amyloidosis undergoing autologous peripheral blood stem cell transplantation, Blood, 2004, 104 (11):1157; DOI: 10.1182/blood.V104.11.1157.1157. ANAND A. et al., CD34+ Selection and (см. прод.) (86) Заявка PCT: C 2 C 2 (85) Дата начала рассмотрения заявки PCT на национальной фазе: 04.07.2018 US 2016/064908 (05.12.2016) (87) Публикация заявки PCT: 2 7 4 7 7 2 8 WO 2017/096347 (08.06.2017) R U 2 7 4 7 7 2 8 Приоритет(ы): (30) Конвенционный приоритет: R U 05.12.2016 (72) Автор(ы): ДЕЛЕЙНИ, Коллин ...

Transgenic mice deficient in T-cells

ヒトｅｐｏを発現する遺伝子改変された非ヒト動物

ARTIFICIAL HUMAN CHROMOSOME CONTAINING HUMAN ANTIBODY lambda LIGHT CHAIN GENE AND NON-HUMAN ANIMAL CONTAINING THE ARTIFICIAL HUMAN CHROMOSOME GENETICALLY TRANSMISSIBLE TO OFFSPRING

【課題】 本発明は、次世代に高効率で子孫伝達可能なヒト人工染色体とその利用方法に関する。 【解決手段】 （a）再配列されていないヒト抗体重鎖遺伝子座、（b）再配列されていないヒト抗体κ軽鎖遺伝子座、および（c）再配列されていないヒト抗体λ軽鎖遺伝子座を保持するヒト抗体産生マウスであって、（a）、（b）および（c）の少なくとも一つがヒト由来染色体断片上に保持されており、（a）、（b）および（c）の少なくとも一つがマウス染色体に挿入されており、さらに少なくとも内因性重鎖の両アレルおよび内因性κ軽鎖の両アレルが不活性化されており、該マウスの血清中にヒト抗体重鎖、ヒト抗体κ軽鎖、およびヒト抗体λ軽鎖を発現する、前記マウス。 【選択図】 図１

Gene therapy for hemophilia A using viral vectors encoding recombinant FVIII variants with increased expression

本公开尤其提供编码在哺乳动物细胞中表达的因子VIII变体的密码子改变的多核苷酸。在一些实施方案中，本公开还提供用于治疗A型血友病的哺乳动物基因疗法载体和方法。在一些实施方案中，本公开提供用于向A型血友病患者给予编码因子VIII多肽的多核苷酸，例如密码子改变的多核苷酸的方法。

Animal model of the human immune system and method for creating it

Transgenic immunodeficient non-human animals

Transgenic non-human animals having genotypes comprising a first DNA sequence encoding an expression regulation sequence for a lymphoid gene operably linked to DNA encoding a lethal polypeptide. Also included are transgenic animals having genotypes comprising the substitution, deletion or insertion of one or more nucleotides in at least one endogenous allele of a CD3-type gene. The transgenic non-human animals have phenotypes characterized by immunodeficiency in at least one function of a lymphoid cell. Such phenotypes include depletion of one or more lymphoid cell types such as T-cells, NK cells, large granular lymphocytes, and/or B-cells. The invention also provides transgenic immunodeficient animals containing a xenograft characterized by a phenotype wherein the animal has an enhanced ability to maintain the xenograft as compared to the maintenance of the xenograft in the species from which the transgenic animal is derived.

Compositions and methods for the treatment and diagnosis of immune disorders

The present invention relates to methods and compositions for the treatment and diagnosis of immune disorders, especially T helper lymphocyte-related disorders. For example, genes which are differentially expressed within and among T helper (TH) cells and TH cell subpopulations, which include, but are not limited to TH0, TH1 and TH2 cell subpopulations are identified. Genes are also identified via the ability of their gene products to interact with gene products involved in the differentiation, maintenance and effector function of such TH cells and TH cell subpopulations. The genes identified can be used diagnostically or as targets for therapeutic intervention. In this regard, the present invention provides methods for the identification and therapeutic use of compounds as treatments of immune disorders, especially TH cell subpopulation-related disorders. Additionally, methods are provided for the diagnostic evaluation and prognosis of TH cell subpopulation-related disorders, for the identification of subjects exhibiting a predisposition to such conditions, for monitoring patients undergoing clinical evaluation for the treatment of such disorders, and for monitoring the efficacy of compounds used in clinical trials.

Methods for the treatment of immune disorders

The present invention relates to methods and compositions for the treatment and diagnosis of immune disorders, especially T helper lymphocyte-related disorders. For example, genes which are differentially expressed within and among T helper (TH) cells and TH cell subpopulations, which include, but are not limited to TH0, TH1 and TH2 cell subpopulations are identified. Genes are also identified via the ability of their gene products to interact with gene products involved in the differentiation, maintenance and effector function of such TH cells and TH cell subpopulations. The genes identified can be used diagnostically or as targets for therapeutic intervention. In this regard, the present invention provides methods for the identification and therapeutic use of compounds as treatments of immune disorders, especially TH cell subpopulation-related disorders. Additionally, methods are provided for the diagnostic evaluation and prognosis of TH cell subpopulation-related disorders, for the identification of subjects exhibiting a predisposition to such conditions, for monitoring patients undergoing clinical evaluation for the treatment of such disorders, and for monitoring the efficacy of compounds used in clinical trials.

Genetically Modified Non-Human Animals Expressing Human EPO

동물 게놈으로부터 인간 EPO를 발현하는 유전자 변형된 비-인간 동물이 제공된다. 또한 그 비-인간 동물 게놈으로부터 인간 EPO를 발현하는 비-인간 동물의 제조 방법, 및 그 비-인간 동물 게놈으로부터 인간 EPO를 발현하는 비-인간 동물의 사용 방법도 제공된다. 이들 동물 및 방법은 많은 기술분야, 이를테면 예를 들어, 인간 적혈구 생성 및 적혈구 기능의 모델화; 적혈구의 인간 병원체 감염의 모델화; 적혈구 생성 및/또는 적혈구 기능을 조절하는 제제들에 대한, 예컨대 건강하거나 병든 상태에서의 생체 내 스크리닝; 적혈구 또는 적혈구 선구 세포에 독성인 제제들에 대한 생체 내 스크리닝; 적혈구 또는 적혈구 선구 세포에 미치는 독성 제제들의 독성 효과에 대해 방지하거나, 완화시키거나 또는 반전시키는 제제들에 대한 생체 내 스크리닝; 질환 치료법에 대한 개체의 반응성을 예측하기 위한 개체로부터의 적혈구 또는 적혈구 선구 세포의 생체 내 스크리닝에서 사용될 수 있다. Genetically modified non-human animals expressing human EPO from the animal genome are provided. Also provided are methods of making a non-human animal expressing human EPO from the genome of the non-human animal, and methods of using the non-human animal expressing human EPO from the genome of the non-human animal. These animals and methods are used in many fields of technology, such as, for example, modeling human erythropoiesis and erythropoiesis function; modeling of human pathogen infection of red blood cells; in vivo screening for agents that modulate red blood cell production and/or red blood cell function, eg, in healthy or diseased states; in vivo screening for agents that are toxic to red blood cells or red blood cell progenitors; in vivo screening for agents that prevent, ameliorate or reverse the toxic effects of toxic agents on red blood cells or red blood cell progenitors; It can be used in the in vivo screening of red blood cells or erythrocyte progenitor cells from a subject to predict the subject's responsiveness to treatment for a disease.

Prokaryotic expression of MHC proteins

The present invention is directed to unglycosylated, prokaryoticauly-expressed MHC polypeptides, methods of producing these polypeptides, and complexes consisting essentially of an isolated MHC component and an antigenic peptide associated with the antigen binding site of the MHC component. These complexes are useful in treating deleterious immune responses, such as autoimmunity.

Patent RU2018124303A3

ВИ“? 2018124303” АЗ Дата публикации: 06.08.2020 Форма № 18 ИЗИМ-2011 Федеральная служба по интеллектуальной собственности Федеральное государственное бюджетное учреждение ж 5 «Федеральный институт промышленной собственности» (ФИПС) ОТЧЕТ О ПОИСКЕ 1. . ИДЕНТИФИКАЦИЯ ЗАЯВКИ Регистрационный номер Дата подачи 2018124303/10(038497) 05.12.2016 РСТ/О$2016/064908 05.12.2016 Приоритет установлен по дате: [ ] подачи заявки [ ] поступления дополнительных материалов от к ранее поданной заявке № [ ] приоритета по первоначальной заявке № из которой данная заявка выделена [ ] подачи первоначальной заявки № из которой данная заявка выделена [ ] подачи ранее поданной заявки № [Х] подачи первой(ых) заявки(ок) в государстве-участнике Парижской конвенции (31) Номер первой(ых) заявки(ок) (32) Дата подачи первой(ых) заявки(ок) (33) Код страны 1. 62/263,470 04.12.2015 05 2. 62/263,573 04.12.2015 05 Название изобретения (полезной модели): [Х] - как заявлено; [ ] - уточненное (см. Примечания) ПРИМЕНЕНИЕ РАЗМНОЖЕННЫХ ПОПУЛЯЦИЙ ГЕМАТОПОЭТИЧЕСКИХ СТВОЛОВЫХ КЛЕТОК/КЛЕТОК-ПРЕДШЕСТВЕННИКОВ Заявитель: ФРЕД ХАТЧИНСОН КЭНСЕР РИСЕРЧ СЕНТЕР, 05 2. ЕДИНСТВО ИЗОБРЕТЕНИЯ [Х] соблюдено [ ] не соблюдено. Пояснения: см. Примечания 3. ФОРМУЛА ИЗОБРЕТЕНИЯ: [Х] приняты во внимание все пункты (см. Примечания) [ ] приняты во внимание следующие пункты: [ ] принята во внимание измененная формула изобретения (см. Примечания) 4. КЛАССИФИКАЦИЯ ОБЪЕКТА ИЗОБРЕТЕНИЯ (ПОЛЕЗНОЙ МОДЕЛИ) (Указываются индексы МПК и индикатор текущей версии) С12М 5/02 (2006.01) 5. ОБЛАСТЬ ПОИСКА 5.1 Проверенный минимум документации РСТ (указывается индексами МПК) С12М 5/02 5.2 Другая проверенная документация в той мере, в какой она включена в поисковые подборки: 5.3 Электронные базы данных, использованные при поиске (название базы, и если, возможно, поисковые термины): Е-Габгагу, Езрасепес, Рабеагсв, РАТЕМТЬСОРЕ, КУРТО, МСВТ, ЕМВГ-ЕВ1, боозе, Сооз]е эспо[аг, РиБМеа, ОРТО, Зслепсе тес 6. ДОКУМЕНТЫ, ОТНОСЯЩИЕСЯ К ПРЕДМЕТУ ПОИСКА Кате- ...

ANIMAL DIFFERENT ANIMALS WITH A HUMANIZED SIGNAL REGULATORY PROTEIN GENE

РОССИЙСКАЯ ФЕДЕРАЦИЯ (19) RU (11) (13) 2018 136 614 A (51) МПК A01K 67/027 (2006.01) ФЕДЕРАЛЬНАЯ СЛУЖБА ПО ИНТЕЛЛЕКТУАЛЬНОЙ СОБСТВЕННОСТИ (12) ЗАЯВКА НА ИЗОБРЕТЕНИЕ (21)(22) Заявка: 2018136614, 23.09.2014 (71) Заявитель(и): РЕГЕНЕРОН ФАРМАСЬЮТИКАЛС, ИНК. (US) Приоритет(ы): (30) Конвенционный приоритет: 23.09.2013 US 61/881,261 2016110462 22.03.2016 (43) Дата публикации заявки: 27.11.2018 Бюл. № (72) Автор(ы): МЕРФИ Эндрю Дж. (US), ТЕРСТОН О. Гэвин (US), ВАРГХЕСЕ Бинду (US), ГУРЕР Каган (US) R U (62) Номер и дата подачи первоначальной заявки, из которой данная заявка выделена: 33 R U (57) Формула изобретения 1. Грызун для экспрессии гуманизированного белка SIRPα, причем геном грызуна содержит замещение экзонов 2, 3 и 4 гена SIRPα грызуна в эндогенном локусе SIRPα грызуна на экзоны 2, 3 и 4 гена SIRPα человека с образованием гуманизированного гена SIRPα, причем указанный гуманизированный ген SIRPα функционально связан с промотором SIRPα грызуна в указанном эндогенном локусе SIRPα грызуна и экспрессирует у указанного грызуна гуманизированный белок SIRPα, содержащий внеклеточную часть белка SIRPα человека, кодируемого указанным геном SIRPα человека, и внутриклеточную часть белка SIRPα грызуна, кодируемого указанным геном SIRPα грызуна, и причем грызуном является крыса. 2. Грызун по п. 1, у которого гуманизированный ген SIRPα содержит экзоны 1, 5, 6, 7 и 8 указанного гена SIRPα грызуна. 3. Грызун по п. 1 или 2, причем указанный грызун не экспрессирует белок SIRPα грызуна. 4. Выделенная клетка грызуна для экспрессии гуманизированного белка SIRPα, причем геном выделенной клетки грызуна содержит замещение экзонов 2, 3 и 4 гена SIRPα грызуна в эндогенном локусе SIRPα грызуна на экзоны 2, 3 и 4 гена SIRPα человека с образованием гуманизированного гена SIRPα, причем указанный гуманизированный ген SIRPα функционально связан с промотором SIRPα грызуна в указанном эндогенном локусе SIRPα грызуна и кодирует гуманизированный белок SIRPα, содержащий внеклеточную часть белка SIRPα ...

Nucleic acids encoding lymphoid CD30 antigen

The description relates to the lymphoid surface antigen CD30 (Ki-1) occurring in Hodgkin's disease, the protein sequence and the associated nucleotide sequence therein, manufacture thereof by genetic engineering, methods for diagnosis and investigation of Hodgkin's disease and use of these nucleotide sequences for producing transgenic animals. The invention provides methods not based on monoclonal antibodies for investigation and diagnosis of anaplastic large-cell lymphomas.

Transgenic mice lacking T-cells

본 발명은 T-세포가 결핍된 유전자 이식 마우스에 관한 것으로 H2K 프로모터에 인간 열충격 단백질(Hsp)의 유전자가 융합된 유전자를 마우스에 이식하므로서 제공된다. 흉선이 위축되고 성숙 T-세포가 검출되지 않는 T-세포가 결핍된 유전자 이식 마우스주(transgenic mice line)를 얻을 수 있었으며, 이는 자가면역질환 발생 기전의 규명 및 면역 억제제의 개발, 새로운 약의 검정 시스템 등의 연구분야에서 유용하게 이용될 수 있다.

Non-human animals having a humanized b-cell activating factor gene

FIELD: biochemistry.SUBSTANCE: invention relates to the field of biochemistry, in particular to a genetically modified rodent animal expressing a humanized Baff protein, as well as a method for its preparation. Genome of the above genetically modified rodent animal comprises replacing the genomic fragment of the endogenous Baff rodent gene with a human genomic fragment containing the exons of the 3–6 human BAFF gene to form a humanized Baff gene. Embryonic stem cell as well as the embryo of the above rodent are also disclosed. Invention also relates to a method for transplanting human cells to the aforementioned rodent.EFFECT: invention makes it possible to efficiently obtain a rodent animal expressing a humanized Baff protein.13 cl, 2 dwg, 4 tbl, 1 ex РОССИЙСКАЯ ФЕДЕРАЦИЯ (19) RU (11) (13) 2 670 016 C1 (51) МПК A01K 67/027 (2006.01) C07K 14/54 (2006.01) C07K 14/705 (2006.01) ФЕДЕРАЛЬНАЯ СЛУЖБА ПО ИНТЕЛЛЕКТУАЛЬНОЙ СОБСТВЕННОСТИ (12) ОПИСАНИЕ ИЗОБРЕТЕНИЯ К ПАТЕНТУ (52) СПК A01K 67/0278 (2006.01); C07K 14/70575 (2006.01); G01N 33/5088 (2006.01) (21)(22) Заявка: 2016123708, 10.11.2014 (24) Дата начала отсчета срока действия патента: Дата регистрации: 17.10.2018 19.11.2013 US 61/905,983 (56) Список документов, цитированных в отчете о поиске: US7759541 B2, 20.07.2010. (45) Опубликовано: 17.10.2018 Бюл. № 29 (86) Заявка PCT: R U 2 6 7 0 0 1 6 C 1 US 2014/064806 (10.11.2014) (87) Публикация заявки PCT: WO 2015/077071 (28.05.2015) Адрес для переписки: 119019, Москва, Гоголевский б-р, 11, этаж 3, "Гоулинг ВЛГ (Интернэшнл) Инк.", Карпенко Оксана Юрьевна (54) ОТЛИЧНЫЕ ОТ ЧЕЛОВЕКА ЖИВОТНЫЕ, СОДЕРЖАЩИЕ ГУМАНИЗИРОВАННЫЙ ГЕН ФАКТОРА АКТИВАЦИИ В-КЛЕТОК (57) Реферат: Изобретение относится к области биохимии, гуманизированного гена Baff. Также раскрыты в частности к генетически модифицированному эмбриональная стволовая клетка, а также животному-грызуну, экспрессирующему эмбрион вышеуказанного грызуна. Изобретение гуманизированный белок Baff, а также к способу также относится к ...

Human CTLA-4 antibodies and their uses

The present invention provides human sequence antibodies against human CTLA-4 and methods of treating human diseases, infections and other conditions using these antibodies.

Transgenic animals bearing human Igλ light chain genes

The invention relates to transgenic animals bearing one or more human λ light chain loci. The invention also relates to methods and compositions for making transgenic animals that have incorporated human λ light chain loci. The invention further relates to methods of using and compositions derived from the transgenic animals that have incorporated human λ light chain loci.

Mice expressing an immunoglobulin hybrid light chain with a human variable region

Transgenic mice depleted in mature t-cells and methods for making transgenic mice

Transgenic mice having a phenotype characterized by the substantial absence of mature T lymphocytes otherwise naturally occurring in said mice. The phenotype is conferred in the transgenic mouse by a transgene contained in at least the precursor stem cell of the T lymphocyte which is depleted. The transgene comprises a DNA sequence encoding a T cell receptor polypeptide variant which inhibits maturation of the T lymphocyte.

Transgenic non-human animals capable of producing heterologous antibodies

The invention relates transgenic non-human animals capable of producing heterologous antibodies and transgenic non--human animals having inactivated endogenous immunoglobulin genes. In one aspect of the invention, endogenous immunoglob-ulin genes are suppresed by antisense polynucleotides and/or by antiserum directed against endogenous immunoglobulins. He-terologous antibodies are encoded by immunoglobulin genes not normally found in the genome of that species of non-human animal. In one aspect of the invention, one or more transgenes containing sequences of unrearranged heterogolous human immu-noglobulin heavy chains are introduced into a non-human animal thereby forming a transgenic animal capable of functionally rearranging transgenic immunoglobulin sequences and producing a repertoire of antibodies of various isotypes encoded by hu-man immunoglobulin genes. Such heterologous human antibodies are produced in B-cells which are thereafter immortalized, e.g., by fusing with an immortalizing cell line such as a myeloma or by manipulating such B-cells by other techniques to perpetuate a cell line capable of producing a monoclonal heterologous antibody. The invention also relates to heavy and light chain immunog-lobulin transgenes for making such transgenic non-human animals as well as methods and vectors for disrupting endogenous im-munogiobulin loci in the transgenic animal.

Generation of xenogeneic antibodies

The subject invention provides non-human mammalian hosts characterized by inactivated endogenous Ig loci and functional human Ig loci for response to an immunogen to produce human antibodies or analogs thereof. The hosts are produced by repetitive transformations of embryonic stem cells by homologous recombination, preferably in conjunction with breeding. Different strategies are employed for recombination of the human loci randomly or at analogous host loci.

Generation of xenogeneic antibodies

Generation of xenogeneic antibodies

The subject invention provides non-human mammalian hosts characterized by inactivated endogenous Ig loci and functional human Ig loci for response to an immunogen to produce human antibodies or analogs thereof. The hosts are produced by repetitive transformations of embryonic stem cells by homologous recombination, preferably in conjunction with breeding. Different strategies are employed for recombination of the human loci randomly or at analogous host loci.

Generation of heterologous antibodies

Generation of xenogeneic antibodies

본 발명은 인간 항체 또는 그것의 제조를 위해 면역원에 대한 반응을 위한 비활성화된 내인성 Ig 유전자좌와 기능성 인간 Ig 유전자좌에 의해 특징 지워지는 비-인간 포유동물 숙주를 제공한다. 숙주는 동종 재조합에 의하여, 바람직하게는 사육과 연관시켜 배 간세포의 반복적인 형질전환에 의하여 생성된다. 인간 유전자좌의 무작위 재조합 또는 유사한 숙주 유전자좌에서의 재조합을 위해서는 상이한 여러 스트래티지가 사용된다. The present invention provides a non-human mammalian host characterized by an inactivated endogenous Ig locus and a functional human Ig locus for response to an immunogen or a human antibody or a preparation thereof. The host is produced by homologous recombination, preferably by repetitive transformation of embryonic stem cells in association with breeding. Several different strategies are used for random recombination of human loci or recombination at similar host loci.

Generation of xenogeneic antibodies

Generation of xenogeneic antibodies

The subject invention provides non-human mammalian hosts characterized by inactivated endogenous Ig loci and functional human Ig loci for response to an immunogen to produce human antibodies or analogs thereof. The hosts are produced by repetitive transformations of embryonic stem cells by homologous recombination, preferably in conjunction with breeding. Different strategies are employed for recombination of the human loci randomly or at analogous host loci.

Generation of xenogenic antibodies

GENERATION OF XENOGENIC ANTIBODIES.

LA PRESENTE INVENCION PROPORCIONA HUESPEDES MAMIFEROS NO HUMANOS CARACTERIZADOS POR LUGARES LG ENDOGENOS INACTIVADOS Y LUGARES LG HUMANOS FUNCIONALES PARA RESPONDER A UN INMUNOGENO PRODUCIENDO ANTICUERPOS HUMANOS O ANALOGOS DE LOS MISMOS. LOS HUESPEDES SE PRODUCEN MEDIANTE TRANSFORMACIONES REPETIDAS DE CELULAS TALLO EMBRIONICAS MEDIANTE RECOMBINACION HOMOLOGA, PREFERENTEMENTE EN COMBINACION CON SU REPRODUCCION. SE EMPLEAN DIFERENTES ESTRATEGIAS PARA LA RECOMBINACION DE LOS LUGARES HUMANOS ALEATORIAMENTE O EN LUGARES ANALOGOS DEL HUESPED. THIS INVENTION PROVIDES NON-HUMAN MAMMARY GUESTS CHARACTERIZED BY INACTIVATED LG ENDOGENOS AND FUNCTIONAL HUMAN LG PLACES TO RESPOND TO AN IMMUNOGEN PRODUCING HUMAN ANTIBODIES OR ANALOGS OF THE SAME. GUESTS ARE PRODUCED THROUGH REPEATED TRANSFORMATIONS OF EMBRYOUS SIZE CELLS THROUGH HOMOLOGICAL RECOMBINATION, PREFERRED IN COMBINATION WITH ITS REPRODUCTION. DIFFERENT STRATEGIES ARE USED FOR THE RECOMBINATION OF HUMAN PLACES RANDOMLY OR IN ANALOG PLACES OF THE GUEST.

Generation of xenogeneic antibodies

Generation of xenogeneic antibodies