Protection of Hepatocyte Transplants by Engineered Veto

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应用于不同的终末期肝病患者。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，并且必须暂时提供。Isogenis的技术基于自然免疫抑制现象。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）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，这些否决载体将CD8 - 1链安装在不同组织表面。在该SBIR的1期研究中，Isogenis证实了用VV转导的小鼠肝细胞在免疫能力强的异体受体中免受排斥反应的保护。此外，还开发了一种新的腺病毒基因转移载体结构。它允许设计临床VV作为完全删除的腺病毒载体，可以在没有辅助病毒的情况下产生。对于SBIR的第2期，Isogenis建议：(1)优化肝细胞转导和移植方案；(2)建立非人灵长类动物（NHP）肝细胞移植模型，以测试临床VVs的功能、药理学和毒性。随着该项目产品开发的临床前阶段的完成，将收集用于veto工程同种异体人肝细胞移植的新药（IND）申请所需的数据。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。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，以进行计划中的研究。

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.