Protection of Hepaticyte Transplants by Engineered Veto

通过工程否决保护肝细胞移植

• 批准号: 7554624
• 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/7554624
• 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 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）：自引入肝移植以来，患者和移植物的预后逐渐改善。全肝或节段性肝移植已被用于治疗各种获得性和遗传性肝病。分离肝细胞输注已被研究作为实体器官移植的替代方法。同种异体肝细胞移植已经成功地减轻了遗传缺陷和肝功能衰竭的症状。在某些情况下，它们可以治愈，在其他情况下，它们可以起到缓解作用，直到获得实体器官。一般免疫抑制方案已被用于保护异体肝组织免受排斥反应。虽然它们很成功，但也有许多严重的副作用。最显著的是，它们会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，即使疗效没有提高，但毒性更小，特异性更高，不抑制保护性免疫反应，充其量只能暂时提供。Isogenis的技术基于自然免疫抑制现象。Isogenis的工程否决使用CD8 ？-链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）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）建立了否决方法的总体可行性。Isogenis现在建议研究肝细胞是否可以用vv转导，并在异体宿主中永久保护免受排斥反应。肝细胞移植可能是理想的模型。肝细胞具有较低的免疫原性，它们可以相对容易地在体外进行操作，并且在大多数情况下，它们的植入不会因潜在的自身免疫性疾病过程而复杂化。Isogenis将为未来的二期SBIR拨款奠定基础，其中Isogenis将使用非人类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。已经开始与美国食品和药物管理局（FDA）讨论VVs及其在移植中的应用。肝脏和肝细胞移植已成功地在患有不同的获得性和遗传性肝病的患者中进行。一般免疫抑制方案已被用于保护异体肝组织免受排斥反应。虽然它们很成功，但也有许多严重的副作用。最显著的是，它们会损害免疫系统的保护功能。Isogenis一直在开发新的治疗方法，以保护同种异体移植物，即使没有提高疗效，但毒性更小，特异性更高，不抑制保护性免疫反应，充其量只能暂时提供。