Protection of Hepaticyte Transplants by Engineered Veto

通过工程否决保护肝细胞移植

• 批准号: 7394544
• 负责人: Uwe D. Staerz
• 金额: $ 18.61万
• 依托单位: ISOGENIS, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7394544
• 关键词: Address; Adenoviruses; Adverse effects; Allogenic; Autoimmune Diseases; CD8B1 gene; Cells; Clinic; Clinical; Clinical Trials; Development; Engineering; Engraftment; Feasibility Studies; Foundations; Future; Genetic; Goals; Grant; Hepatocyte; Homologous Transplantation; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunologic Adjuvants; Immunologist; In Vitro; Infusion procedures; Islets of Langerhans; Islets of Langerhans Transplantation; Knowledge; Liver; Liver Failure; Liver diseases; Mission; Modeling; Mus; Mutation; Organ; Organ Transplantation; Outcome; Patients; Pharmacology; Phase; Physicians; Population; Process; Protocols documentation; Relative (related person); Satellite Viruses; Scientist; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Solid; Spleen; Staging; Surface; Symptoms; System; T-Lymphocyte; Technology; Testing; Tissues; Toxic effect; Transplantation; Treatment Protocols; United States Food and Drug Administration; antibody engineering; base; cell transformation; design; experience; immunogenicity; imprint; improved; in vivo; liver transplantation; nonhuman primate; novel therapeutics; preclinical study; research study; vector

DESCRIPTION (provided by applicant): Since the introduction of liver transplantation, patient and graft outcomes have incrementally improved. Whole liver or segmental liver transplantation have been performed in patients suffering from different acquired and genetic liver diseases. The infusion of isolated hepatocytes has been investigated as an alternative to solid organ grafting. Transplantations of allogeneic hepatocytes have been successfully performed to alleviate symptoms of genetic defects and liver failures. They were curative in some cases and provided reprieve in other cases until solid organs became available. General immune suppression regimens have been used to protect allogeneic liver tissues from rejection. Though successful, they are fraught by many grave side effects. Most prominently they impair the protective functions of the immune system. Therefore, major efforts are being made to introduce novel therapeutics that protect allogeneic grafts with similar, if not improved efficacy, yet that are less toxic, highly specific, do not suppress protective immune responses and at best have to be provided transiently. Isogenis bases its technology on the natural veto immune inhibitory phenomenon. Isogenis' engineered veto uses the surface expression of the CD8 ?- chain to transform cells and cells into specifically immune suppressive entities. Isogenis believes that its veto technology will change the paradigm of immune suppression from systemic (general) to tissue specific (tissue centered). Isogenis' scientists established the overall feasibility of the veto approach with engineered antibodies and different veto vectors (VV). Isogenis now proposes to examine whether hepatocytes can be transduced with VVs and can be permanently protected from rejection in allogeneic hosts. Hepatocyte transplantation may represent the ideal model. Hepatocytes are of low immunogenicity, they can be manipulated ex vivo with relative ease and in most cases their engraftment is not complicated by underlying autoimmune disease processes. Isogenis will lay the foundation for a future Phase II SBIR grant, in which Isogenis will use a nonhuman primate model to test the functionality, pharmacology and toxicity of a clinical VV and thus will aim to complete the pre-clinical trial stage of hepatocyte transplantation. Discussions with the Food and Drug Administration (FDA) about VVs and their use in transplantation have been initiated. Liver and hepatocyte transplantations have successfully been performed in patients suffering from different acquired and genetic liver diseases. General immune suppression regimens have been used to protect allogeneic liver tissues from rejection. Though successful, they are fraught by many grave side effects. Most prominently they impair the protective functions of the immune system. Isogenis has been developing novel therapeutics that protect allogeneic grafts with similar, if not improved efficacy, yet that are less toxic, highly specific, do not suppress protective immune responses and at best have to be provided transiently.

描述（由申请人提供）：自从引入肝移植以来，患者和移植物的结果逐渐改善。患有不同获得性和遗传性肝病的患者已经进行了全肝或部分肝移植。已研究了分离肝细胞的输注作为实体器官移植的替代方法。同种异体肝细胞移植已成功用于缓解遗传缺陷和肝衰竭的症状。它们在某些情况下具有治愈作用，在其他情况下可以提供缓刑，直到实体器官可用为止。一般免疫抑制方案已用于保护同种异体肝组织免受排斥。尽管取得了成功，但它们也充满了许多严重的副作用。最显着的是，它们损害免疫系统的保护功能。因此，人们正在努力引入新的治疗方法，以保护同种异体移植物，即使没有改善，也具有相似的功效，但毒性较小，高度特异性，不会抑制保护性免疫反应，并且最多只能暂时提供。 Isogenis 的技术基于自然否决免疫抑制现象。 Isogenis 的工程否决利用 CD8β-链的表面表达将细胞和细胞转化为特异性免疫抑制实体。 Isogenis 认为，其否决技术将改变免疫抑制的范式，从系统性（一般性）到组织特异性（以组织为中心）。 Isogenis 的科学家利用工程抗体和不同的否决载体 (VV) 确定了否决方法的总体可行性。 Isogenis 现在提议检查肝细胞是否可以用 VV 转导，并可以永久保护其免受同种异体宿主的排斥。肝细胞移植可能代表了理想的模型。肝细胞具有低免疫原性，它们可以相对容易地离体操作，并且在大多数情况下，它们的植入并不因潜在的自身免疫性疾病过程而复杂化。 Isogenis 将为未来的 II 期 SBIR 拨款奠定基础，其中 Isogenis 将使用非人灵长类动物模型来测试临床 VV 的功能、药理学和毒性，从而旨在完成肝细胞移植的临床前试验阶段。与美国食品和药物管理局 (FDA) 就 VV 及其在移植中的应用进行的讨论已经开始。已经在患有不同获得性和遗传性肝病的患者中成功进行了肝脏和肝细胞移植。一般免疫抑制方案已用于保护同种异体肝组织免受排斥。尽管取得了成功，但它们也充满了许多严重的副作用。最显着的是，它们损害免疫系统的保护功能。 Isogenis 一直在开发新的疗法来保护同种异体移植物，其功效即使没有提高，也具有相似的效果，但毒性较小，特异性强，不会抑制保护性免疫反应，并且最多只能暂时提供。