Apherese-vorrichtung

The invention concerns a Apherese device, comprehensively a firm carrier contactable with the Blutoder plasma river. By Apherese treatment procedures are understood, whose therapy effects extrakorporalen on the s elimination of pathogener proteins, protein-bound pathogener substances, free pathogener substances or pathogener cells of the blood to be based. If the pathogene protein can be eliminated only from the cell-free plasma, the plasma is separated before from the blood cells with the help of a diaphragm plasma separator (Plasmaseparation) or with the help of a Hämozentrifuge. With the unselektiven plasma exchange (Plasmapherese) the exchanged patient plasma is separated as entire, whereby beside the Pathogenen also all other vitally necessary proteins are eliminated. Thus substituting of the taken plasma with electrolytes, human albumin or fresh plasma is necessary. With selective Plasmaphereseverfahren pathogene proteins can be completely specifically removed from the separated plasma by adsorption, Präzipitation or filtration, whereby is the plasma can be clean-founded after the distance without substantial volume loss. These selective procedures have the advantage that here without a substitution solution can be done. With selective Vollblutaphereseverfahren the pathogenen proteins are specifically adsorbed and without previous Plasmaseparation directly from the not pre-treated blood, with which - contrary to the plasma ready ion procedures - both the Plasmaseparation and the addition of a substitution solution can be void. A further Unterform of the Apherese is the Zytapherese, with which cells from the blood are removed. Can be won selectively leukocytes, erythrocytes, Thrombozyten, Granulozyten or even main cells. at present 2s although the Apherese (e.g. as Plasmapherese or Zytapherese) for the production by donor plasma (when plasma canned goods, for the isolation of different plasma parliamentary groups or for the production of blood products) is predominantly used, wins Aphereseverfahren increasingly also on therapeutic area in meaning. Thus at present a whole series of metabolic diseases (e.g. (family) Hypercholesterinämie become, koronare heart illness with insulating LP (A) progrediente - increase, Chylomikronämie syndrome, liver failure,…), Kidney diseases (Goodpasture syndrome, systemic Lupus of erythematodes with Lupusnephritis, Wegner Granulomatose, Hämolytisch uraemic syndrome, Idiopathi fokal sklerosierende Glomerulonephritis, Paraproteinämie associated syndromes, Kryoglobulinämi Purpura, HLA sensitization with Nierentransplantation,…), Illnesses of the nervous system (Myasthenia grave, Guillain Barri syndrome, chronic demyelinisierende PolyradikuIoneuritis, Paraproteinämi Polyneuropathie, Lambert Eaton syndrome, Refsum syndrome,…), Illnesses of the immune system (Rheumatoide Arthritis, Hemmkörperhämophilie, Pemphigus…. ), illnesses of the Blutkreislaufs and the micro circulation (hyperviscosity syndrome, Antiphospholipidantikörper syndrome, Thromboti Mikroangiopathie after Knochenmarktransplantation, age-dependent Makuladegeneration, hearing fall, peripheral disturbances of the micro circulation, Idiopathi dilatative Kardiomyopathie, Transplantatvaskulopathie after Herztranspantation, Homozygote family Hypercholesterinämie, Fokal segmentale Glomerulosklerose, Hämolytisch uraemic syndrome…. ), poisonings, acute liver insufficiency, Neoplasmen, hyperhydration, Thyreotoxikose, etc., treated with Aphereseverfahren (see Pschy4s rembel (257. Edition) keyword ùPlasmapherese "; www.nephrologie.de/172Apharese.htm). The Alzheimer' illness (AE) is a progressive, neurological disturbance for those at present no effective treatment possible is. For this illness cerebral Plaques, which contains the Amyloid E Peptid, is typical, and threadlike neural structures from so the Mikrotubulus associated rope protein. Although both Amyloid-J3 and ROPE for the pathogenesis are relevantly regarded and, the most current research results seem to point to the fact that Amyloid-13 represents the priority agent in the pathogenesis. From there increasingly Therapeutika are developed, those the Amyloid E production, which Amyloid aggregation or the neurotoxic occurrences caused by these aggregates is to prevent ss. A recapitulatory representation of the therapeu3 RK 413,336 B tables strategies for AE, hit so far, is given in the overview article of wolf (Nature Reviews Drug Discovery 1 (2002) 859-866). The Amyloid E Plaques forms on the basis of the AmyloidPrecurser so called protein (APP), which is an integral a Transmembran protein (for also no physiological function is clearly occupied; however newest research results let assume that APP functions as so-called diaphragm cargo receptor for Kinesin I). APP is proteolytically split by Sekretasen so called, whereby physiologically above all a 40-Aminosäuren long AI3Peptid (Al 40) is formed. Others, shorter and longer forms of AI develop likewise, above all a 42-Aminosäure-Version (A “=), which exhibits a high aggregation ability. This A1342 - Form is from there also the predominant form in amyloiden Plaques. For these different splitting the responsible persons Sekretasen (A, and above all [3und gamma Sekretase) from there also primary attack targets of a possible AE treatment strategy form. It was tried to use modulators and/or inhibitors for these enzymes with the treatment of AE (like e.g. Benzodiazepine, Sulphonamide, Benzocaprolactame). A further gene, which is associated with AE, is Apolipoprotein E, whereby for this three alleles variants exist (APOE2, APOE3 and APOE4). It was shown the fact that persons exhibit also or two copies of APOE4 a higher risk for AE, whereas APOE2-Träger a smaller risk, compared to which exhibits total population. Also shows it itself that persons, who take Statine, thus drugs, which inhibieren Cholesterinbiosynthese, to itself, a clearly reduced risk for AE exhibit. A further strategy for the treatment of AE concentrates from there on the inhibition of the Cholesterinbiosynthese, evenly with for example Statinen. A further beginning for the treatment of AE concerns the inhibition of the Amyloid aggregation in cerebral Plaques, which Sekretase lnhibitoren among other things likewise through be accomplished could. Further also one suggested lowering the zinc content since zinc in physiologically relevant concentrations can induce the aggregation of AI3. Finally also immunological strategies were described, for example a Immunisierung with A1 42, which however in the context of of a clinical study because of heavy side effects to be adjusted had (Willke, picture of the science, 9 (2003), 24-28). Further AE-Behandlungsstrategien, which was suggested while stationary to the technology, concerns the prevention of the APP Expression and the increase of the AI3-Clearance, whereby for first substances were looked for, which interact with the APP Promoter region. Regarding the Clearance an increase of the activity of certain Proteasen, like the insulin reducing enzyme and Neprolysin, was suggested or the peripheral application by anti-AI3Antikörpern (De Mattos et al., PNAS 98 (15) (2001), 8850-8855). Finally was also tried to dissolve Amyloid Plaques already existing again for example by degradation of the Amyloid - levels in the serum of AE-patients. In this connection it was also suggested reducing the Plaque deposits of 13-Amyloid-Proteinen in the brain by Apherese procedures (US 6,551,266, where the distance of macromolecules with a molecular weight of more than 500kD is suggested by Apherese), without this was also actually shown however for AE. The dissolution by Plaques in brain cells, already existing, is directly not possible however by Aphereseverfahren (blood/brain barrier is insurmountably for Plaques or also molecules with > 500kD). The WHERE 97/48483 concerns affinity diaphragm systems for blood cleaning. Task of the available invention was from there the supply new Behandlungsund prevention strategy for the Alzheimer' illness. Accordingly with the available invention a Apherese device, comprehensively a firm carrier contactable with the blood or plasma river, which a Amyloid - Precurser4 RK 413,336 B protein (APP) binding receptor exhibits, is made available. With the available Apherese device purposefully a Clearance can be made by APP or APP Abbauprodukten, in particular AI3 “o or AI342, with AE-patients and/or persons with AE-risk by means of Apherese. It is well-known that a dynamic Äquilibrium of AI3 “2 between the central nervous system (ZNS) and the plasma exists. It could be shown in the mouse model (DeMattos PNAS 2001, see above) that the peripheral application of anti-as antibodies and the plasma A 42 overcome the ZNS that the anti-on antibodies the blood Him barrier. These results became from Matsuoka et al. (Joumal OF Neuroscience 2003:29 - 33) by the peripheral application of other AI342 in the brain can thus by interception of A 42 critical whether the receptors in the Apherese device, which are contacted with the blood or plasma of the patient specifically for AI342 substantial it is only that with this specific adsorption APP and its (proteolytic) are eliminated dismantling products, in particular A 42, from the blood, so that it does not come to a ùfalschen " protein dismantling (to AI342). Thus the available invention is based on completely different application beginning for the Apherese than US 6,551,266, i.e. on the elimination of the potenziellen Plaque components and not only the Plaques. In all other respects the elimination of Plaques is not ruled out from the beginning by means of Apherese as effectively to the AEBehandlung, since the blood Apherese cannot at all reach the regions of the Plaqueentstehung in the brain. On the other side the Apherese according to invention has those in relation to procedures, in the body for the depletion of AI leads (like e.g. in DeMattos et al., PNAS 98 (15) (2001), 8850-8855 with peripheral anti- A antibodies), the crucial advantage that here no autoimmune answers can be released. Further also according to invention no substances must be supplied to the patient, those only in the body be worked can (possibly only, after it transported to a certain place), but the pathogene agent purposefully removed, the cause of the illness specifically extrakorporal are thus separated, without the reaction products in the body must be eliminated. And the well-known AphereseVorrichtungen in all execution forms, already existing, can be adapted according to invention easily to the available invention. In particular medicine-technical suitability consideration should be taken with the choice of the firm carrier (and the Apheresevorrichtung) on its (of them). Such carriers, procedures or devices are among other things in US 5,476,715, 6,036,614, 5,817,528 or 6,551,266 descriptive. Appropriate ones commercial Apherese apparatuses become also among other things of the companies Fresenius, Affina, plasma SELECT, ASAHI, Kaneka, brown, etc. driven out, like e.g. the LDL Therasorb®, the Immunosorba®, the Prosorba®, the Globaffin®, the industrial union-Therasorb®, the Immusorba®, the Liposorba®, the HELP®, the DALI®, the BilirubinGallensäure absorbers the BR-350, the Prometheus® decontamination, the MARS®, the ADAsorb system of Medicap or the plasma FLO system. All these systems - although in the commercial form not primarily always directed toward the specific elimination of individual protein - can be adapted easily by a Apherese specialist to the available invention, e.g. as Immunapherese and/or under installation of the firm carrier according to invention (e.g. as column) into the Apherese equipment. Under, APP binding receptors " are understood from there also according to invention all substances, which have an affinity for the ligands APP and its biological by-products, in particular A1 42, and able are to remove these Polypeptide from the blood or plasma from AE-patients or persons with a risk for AE. This APPbzw. AI342 - Receptors can preferably be thereby (poly or monoclonal) antibodies, proteins, Peptide, Ganglioside or nucleic acids. Are particularly preferential thereby anti- APP antibodies, anti-AI340-Antikörper or anti- A 42 - RKs 413,336 B antibody, APP binding proteins, in particular Gelsolin, apoJ or apoE, APP binding Peptide, APP binding Ganglioside, in particular GM1, or APP binding nucleic acids, in particular Aptamere) or mixtures of these receptors. Examples of such antibodies are 3D6 (A 1 .s), 2H3 (A 1,-12), 2G3 (AJ330), 21F12 (A 33,-42), 12H7 (AJ33 z) (Johnson Wood et al., PNAS 1997:1550 - 1555), 10D5, 16C11 (Bard et al., Nature Medicine 2000:916 - 919) De Mattos the et al. (2001) descriptive antibody (m266, m243) as well as antibody of same Spezifltät. Such antibodies will receive APP, AI342 or variants for example with the Immunisierung from mammals with Vakzinformulierungen, containing from it, if necessary followed from cell fusion and clone lesson minutes (with monoclonal Antikörpem). Gelsolin (Matsuoka et al. 2003, see above), apoJ and apoE (DeMattos et al. 2001, see above) are further examples of APP binding protein receptors. GM1 is an example of a APPbindenden Gangliosid receptor (Matsuoka et a12003, see above). Peptide as APP binding receptors can be compound thereby from Doder L-amino acids or combinations of D and L-amino acids, and if necessary by further modifications, Ringschlüsse or Derivatisierungen to have been changed. Suitable Peptidrezeptoren for e.g. AI342 is commercially available. Preferably these Peptide are at least 5, preferably 6, amino acids long, in particular at least 8 amino acids, whereby preferential lengths can extend up to 11, preferably up to 14 or 20 amino acids. According to invention however also longer Peptide can be consulted easily than APP binding receptors. Further Oligomere (like e.g. Polyethylenimin and Polylysin) are suitable as receptors. For the production of such APP binding receptors are naturally also phage libraries, Peptid libraries (see above) or structural libraries, e.g. by means of combinatorial chemistry produced or by means of high throughput screening techniques for most diverse structures received, suitable. Further receptors on basis of nucleic acids (ùAptamere, also APP binding, can "; in addition, ùDecoy " - Oligodeoxynuleotide (DS Oligonukleotide, which represent connection places for Transkriptionsfaktoren from the sequence)) is used, whereby also these can be found with most diverse (Oligonukleotid) libraries (e.g. with 2-180 nucleic acid remainders) (e.g. Burgstaller et al., Curr. Opin. Drug Discov. Dev. 5 (5) (2002), 690-700; Famulok et al., Acc. Chem. Res. 33 (2000), 591-599; Mayer et al., PNAS 98 (2001), 4961-4965, uvm.). The nucleic acid backbone can be found thereby for example by the natural Phosphordiester connections in addition, by Phosphorotioate or combinations or chemical variations (e.g. as PNA), whereby as bases above all according to invention U, T, A, C, G, H and mC to be used to be able. The 2 ' - remainders of the nucleotides, which can be used in accordance with the available invention, are preferably H, OH or or other groups of protection and modifications to the 2 ' - position, whereby nucleic acids can be also modified, thus for example with groups of protection, how they are usually used in the Oligonukleotidsynthese, to be provided. By ùSchutzgruppe " thereby a Veretherung of the oxygen atom is understood, whereas at the 2 ' - modification - OH-group through something else one replaces. For both variants while stationary the technology very various possibilities exist, particularly preferential groups of protection are thereby methyl, allyl, Propyl, and such (thus e.g. 2 ' - OCH3, 2 ' - O-CH=CH2, etc.); particularly preferential modifications are 2 ' - Desoxy, 2 ' - Amino, 2 ' - Fluoro, 2 ' - Bromo, 2 ' - Azido, in addition, metals, as are, etc. Further also according to invention the Olig°nukle°tid'Stabilisierungstechniken' can for the anti-scythe technology (Ribozyme, RNAi, etc.) was developed, for the supply of nucleic acids to be consulted (s. e.g. the companies ISIS and Ribozyme Pharmaceuticals, in particular their patent documents and homepage leading thereby). 6 RKs 413,336 B APP binding Aptamere (those according to invention like defined above also AI34 z binding Aptamere close) are from there likewise preferential APP binding receptors in the context of the available invention. From there the APP binding receptors which uses patients of Peptiden, Antikörpem or nucleic acids to preferably consist, to a suitable substrate for the extrakorporalen elimination of APP and its proteolytic dismantling products in Alzheimer (risk, become according to invention). With the application of the available invention in medical routine practice it is necessary that the carrier is sterile and pyrogenfrei, so that each support and/or each receptor/carrier combination, which fulfills these characteristics, is preferential according to invention (e.g. see. US 6,030,614 or US 5,476,715). If necessary among the suitable examples ranks porous Homopolymere, Cooder Terpolymere of Vinyl containing monomers (e.g. AcryI acid, like e.g. TSK Toyopearl, Fractogel TSK), carriers with modifications (activations) with Oxiran containing connections (e.g. Epichlorohydrin) and further reactions with NH3, Amino or carboxyl containing connections, or CNBr or CNCI Adsorbientien, as in the EP 110,409 A and the DE 36 17 672 A described. Particularly preferential adsorption materials for therapeutic purposes are not suitable to avoid a loss from blood cells to activate the complement system or only slightly and keep an aggregate formation in the extrakorporalen cycle if possible hintan. Further the assigned substrates should be preferably also in receptor-coupled form sufficiently stably in relation to sterilization measures, in particular opposite ethyl oxide saturation, GlutaraldehydSättigung, gamma ray exposure, steam curing, UV treatment, solvent treatment and/or Detergensbehandlung, etc. For example also products on Sepharose, Agarose, acrylic, Vinyl, Dextranetc can. - Basis to be used, which exhibit preferably suitable functional groups for the binding of the APP binding receptors already commercially available. Further suitable carriers close also Monolithe (carriers on basis of transverseinterlaced Glycidylmethacrylat CO ethylenglykoldimethacrylat polymer). For the coupling of the receptors to the suitable carriers those is usable e.g. the specialist well-known chemistry (Bioconjugate Techniques, Greg T Hermanson, OD., Academic press, Inc., San Diego, APPROX., 1995, 785pp). In accordance with a further aspect the available invention concerns the use of the device according to invention to the supply of a treatment or treatment device of the Alzheimer' illness or for the prevention of a such illness, as the device is prepared suitably for the treatment of the respective patient. At the time of the execution of the treatment a patient for a length of time sufficient for the effective elimination of APPPolypeptiden is attached to the Apherese equipment, whereby the Blutoder plasma river of the patient with the firm carrier, comprehensively the APP binding receptor, is contacted, on which APP and/or the proteolytic dismantling products are bound by APP, in particular AI342. In the course of the Apherese treatment naturally peripheral or centralvenous Venenzugang and/or arterievenöse Fistel is to be guaranteed to note just like sufficient anti-coagulation, as well as necessary Quantifizierungsund measuring data. Further with most Apherese procedures a primary separation from plasma and blood cells before the actual plasma treatment will be necessary. Special persons, with whom a preventive measure is necessary, are familiar burdening persons, older persons (> 50, > 60 or > 70 years) or persons with another factor of risk for AE, in particular genetic factors. The invention is described on the basis the following examples, to which it is naturally reduced, more near. 1. Production the APP receptor of the basic carrier 7 RKs 413,336 B 1,1 monolithic column a CIM® Epoxy Monolithic column (BIA of separate ion, SI) is äquilibriert in accordance with the data of the manufacturer with 0,5 M well phosphate buffers at pH 8.0 and a monoklonarer antibody against AI3 Peptid in accordance with manufacturer data is likewise activated and coupled to the CIM column. The column is several times washed with phosphate buffer (+ 1 M NaCI) and surplus Epoxy groups if necessary still blocked. Quality assurance is accomplished by means of control in Waschund Äquilibrationseluat; only columns without active Epoxy groups and without Antikörper Leakage in the Eluat are re-used and built into Apharese equipment. 1,2 Sepharose column a Agarose Bulk material (Sepharose CL4B) aseptisch into a sterile and pyrogenfreien container and the material is filled is aseptisch washed, whereby between each wash step the gel material is dried completely under vacuum. The Sepharose is steam-sterilized afterwards for minutes with 115°C in autoclaves. After sterilization the Sepharose is taken up in a sterile container to 60% AcetonNVasser and activated with CNBr and tri ethyl amine (14 g CNBr per 96 ml Acton; 30 ml tri ethyl amine in 66,2 ml 87% igem acetone). Then a Aceton/HCI solution was added (392 ml sterile, pyrogenfreies water; 16,3 ml 5 N HCI, 408 ml acetone). The activated Sepharose is washed and supplied within 2 h of the coupling reaction, in order to prevent the hydrolysis from activated groups to. A sterile-filtered anti-body solution (m266 and/or m243) is brought into the reaction container and agitated for at least 90 min. Finally the reaction solution is thoroughly washed (with isotonischem phosphate buffer), until no reaction products in the Eluat is provable, and the anti-body-coupled Sepharose filled into sterile and depyrogenisierte glass columns with glass sinters and submitted of a concluding quality control (Eluatanalyse regarding reaction products, heavy metals etc.; Particle analysis, Pyrogenizität; Sterility). 2. Animal model for the Apherese treatment of Alzheimer patients in the last years is at the Gerhardt Katsch " - DE, a special extrakorporales system for experimental Apherese in freely mobile small animals diabetes lnstitut developed in Karl castle. Thus a Apherese treatment can be made repetitive to the same animal. The assigned animals can in addition also still to follow-up studies for the long-term evaluation of the Apherese therapy to be taken up. The application of this experimental Apherese system was successfully demonstrated at different rat trunks. Repetitive Apherese treatment was well stood in rats with type IDiabetes and Kollagen type of Ii-induced Arthritis, if their body weight lay over 250 g. Before beginning of the experimental Apherese therapy the animals are provided with arterial and venous Kathedem. In a first step with the Apherese first blood cells and plasma by means of plasma filters are separated. While the blood cells are refundiert directly into the animal (over the venous Katheder) the separate plasma led past the adsorbent manufactured in example 1 (whereby the ligands are separated by connection to the immobilized receptors from the plasma), before it is again supplied to the animal. 8 RKS 413,336 B