Protection of Hepatocyte Transplants by Engineered Veto

描述（由申请人提供）：自从引入肝移植以来，患者和移植物结局逐渐改善。全肝或节段性肝移植已在不同终末期肝病患者中实施。已经研究了分离肝细胞的输注作为实体器官移植的替代方法。同种异体肝细胞的移植已经成功地进行，以减轻遗传缺陷和肝功能衰竭的症状。在某些情况下，这些治疗是治愈性的，而在另一些情况下，这些治疗提供了缓刑，直到有实体器官可用。一般免疫抑制方案已被用于保护同种异体肝组织免受排斥。虽然成功，但它们充满了许多严重的副作用。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的治疗剂，其保护同种异体移植物具有相似的（如果不是改善的）功效，但毒性较小、高度特异性、不抑制保护性免疫应答并且必须瞬时提供。Isogenis的技术基于自然否决免疫抑制现象。Isogenis的工程否决利用CD 8 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模式，从系统性（一般）到组织特异性（组织中心）。Isogenis的科学家们利用工程抗体和不同的否决载体（VV）建立了否决方法的整体可行性，这些否决载体将CD 8 1-链固定在不同组织的表面上。在该SBIR的第1阶段，Isogenis确定了用VV转导的小鼠肝细胞在免疫活性同种异体受体中免受排斥反应。此外，还开发了一种新的腺病毒基因转移载体结构。它允许将临床VV设计为可以在没有辅助病毒的情况下产生的完全缺失的腺病毒载体。对于本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，以检测临床VV的功能性、药理学和毒性。由于该项目正在完成产品开发的临床前阶段，因此将收集用于移植经兽医工程改造的同种异体人肝细胞的研究性新药（IND）申请备案所需的数据。已经开始与美国食品药品监督管理局（FDA）讨论VV及其在移植中的使用。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，以执行计划的研究。 公共卫生相关性：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同种异体肝组织免受排斥。虽然成功，但它们充满了许多严重的副作用。最突出的是，它们损害免疫系统的保护功能。Isogenis一直在开发新的治疗方法，以类似的方式保护同种异体移植物，如果没有提高疗效，但毒性较小，高度特异性，不抑制保护性免疫反应，最好是暂时提供。

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.