Protection of Hepatocyte Transplants by Engineered Veto

工程否决对肝细胞移植的保护

• 批准号: 7801164
• 负责人: Uwe D. Staerz
• 金额: $ 65.17万
• 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 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7801164
• 关键词: Adenovirus Vector; Adjuvant; Adverse effects; Allogenic; Animals; Architecture; CD8B1 gene; Cell surface; Cells; Clinical; Collaborations; Data; Engineering; Ensure; Gene Transduction Agent; Generations; Genetic; Graft Survival; Grant; Helper Viruses; Hepatocyte; Homologous Transplantation; Human; Human Engineering; Immune; Immune response; Immune system; Immunosuppression; Infusion procedures; Investigational Drugs; Investigational New Drug Application; Lead; Liver; Liver Failure; Liver diseases; Macaca mulatta; Malignant - descriptor; Medical center; Modeling; Mus; Mutation; Organ; Organ Transplantation; Outcome; Patients; Pharmacology; Phase; Production; Protocols documentation; Regimen; Research; Research Personnel; Scientist; Small Business Innovation Research Grant; Solid; Staging; Surface; Symptoms; Technology; Testing; Tissue Engineering; Tissues; Toxic effect; Transplantation; Treatment Protocols; United States Food and Drug Administration; Universities; Vaccination; antibody engineering; base; cell transformation; design; fully-deleted adenoviral vector; gene therapy; gene transfer vector; immunogenicity; imprint; improved; in vivo; liver transplantation; nonhuman primate; novel; novel strategies; novel therapeutics; pre-clinical; product development; public health relevance; 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 endstage 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 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 1-chain to transform 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) that mounted the CD8 1-chain on the surface of different tissues. In Phase 1 of this SBIR, Isogenis established that mouse hepatocytes transduced with a VV were protected from rejection in immune competent allogeneic recipients. In addition a novel architecture of Adenoviral gene transfer vectors was developed. It allowed the design of a clinical VV as a fully deleted Adenoviral vector that could be produced without a helper virus. For Phase 2 of this SBIR, Isogenis proposes to (I) to optimize hepatocyte transduction and transplantation protocols and (II) to establish a nonhuman primate (NHP) hepatocyte transplantation model to test the functionality, pharmacology and toxicity of clinical VVs. As the pre-clinical stage of product development is being completed with this project, data necessary for the filing of an investigational new drug (IND) application will be collected for the transplantation of veto-engineered allogeneic human hepatocytes. Discussions with the Food and Drug Administration (FDA) about VVs and their use in transplantation have been initiated. A collaboration between Isogenis' basic scientists (VV production, mouse studies) and University of Pittsburgh Medical Center's clinical researchers (NHP studies, transduction of human cells) has been established to perform the planned studies. PUBLIC HEALTH RELEVANCE: 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。对患有不同终末期肝病的患者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，不抑制保护性免疫反应，并且必须暂时提供。 Isogenis 的技术基于自然否决免疫抑制现象。 Isogenis 的工程否决利用 CD8 1 链的表面表达将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 的科学家利用工程化抗体和将 CD8 1-链安装在不同组织表面的不同否决载体 (VV) 确定了否决方法的总体可行性。在该 SBIR 的第一阶段，Isogenis 证实用 VV 转导的小鼠肝细胞在具有免疫能力的同种异体受体中可以免受排斥。此外，还开发了一种新型腺病毒基因转移载体结构。它允许将临床 VV 设计为完全删除的腺病毒载体，无需辅助病毒即可生产。对于该 SBIR 的第 2 阶段，Isogenis 建议 (I) 优化肝细胞转导和移植方案，以及 (II) 建立非人灵长类动物 (NHP) 肝细胞移植模型以测试临床 VV 的功能、药理学和毒性。随着该项目的产品开发临床前阶段即将完成，将收集提交研究性新药 (IND) 申请所需的数据，用于移植否决工程同种异体人类肝细胞。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。 Isogenis 的基础科学家（VV 生产、小鼠研究）和匹兹堡大学医学中心的临床研究人员（NHP 研究、人类细胞转导）之间的合作已经建立，以执行计划的研究。 公共健康相关性：已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。