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）：由于引入肝移植，患者和移植结果已逐步改善。患有不同性疾病和遗传性肝病的患者已经进行了整个肝或节肝移植。已经研究了分离的肝细胞的输注，以替代固体器官嫁接。同种异性肝细胞的移植已成功进行，以减轻遗传缺陷和肝衰竭的症状。在某些情况下，它们是治愈性的，在其他情况下可以缓刑，直到可用的器官可用为止。一般的免疫抑制方案已用于保护同种异体肝组织免受排斥。尽管成功，但它们受到许多严重的副作用的困扰。最突出的是它们损害免疫系统的保护功能。因此，正在做出重大努力来引入新型的治疗剂，以保护具有相似功效的同种异体移植物，即使没有提高功效，但毒性较小，高度特异性，不能抑制保护性免疫反应，充其量必须暂时提供。 Isogenis将其技术基于自然否决免疫抑制现象。 Isogenis的工程化否决权使用CD8的表面表达？ - 将细胞和细胞转化为特定的免疫抑制实体。 Isogenis认为，其否决技术会将免疫抑制的范式从系统（一般）变为组织特异性（组织中心）。 Isogenis的科学家通过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现在建议检查是否可以用VV转导肝细胞，并可以永久保护脱离同种异体宿主中的排斥。肝细胞移植可能代表理想模型。肝细胞的免疫原性低，可以相对轻松地进行离体操纵，并且在大多数情况下，由于自身免疫性疾病过程的基本，它们的植入并不复杂。 Isogenis将为未来的II期SBIR赠款奠定基础，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，因此旨在完成肝细胞移植前临床前试验阶段。与食品药品监督管理局（FDA）讨论有关VVS及其在移植中的使用。肝脏和肝细胞移植已成功进行，患有不同性疾病和遗传性肝病的患者。一般的免疫抑制方案已用于保护同种异体肝组织免受排斥。尽管成功，但它们受到许多严重的副作用的困扰。最突出的是它们损害免疫系统的保护功能。 Isogenis一直在开发新型的治疗剂，这些治疗疗法可以保护具有相似功效的同种异体移植物，但毒性较小，高度特异性，不能抑制保护性免疫反应，并且充其量必须暂时提供。