Protection of Hepatocyte Transplants by Engineered Veto

描述(由申请人提供)：自从引入肝移植以来，患者和移植物的结果逐渐改善。对不同终末期肝病患者进行了全肝或节段性肝移植。输注分离的肝细胞作为实体器官移植的替代方法已被研究。同种异体肝细胞移植已经成功地用于缓解遗传缺陷和肝功能衰竭的症状。它们在某些情况下是治愈的，在其他情况下提供缓刑，直到固体器官可用。一般的免疫抑制方案已被用于保护同种异体肝组织免受排斥反应。尽管取得了成功，但它们也存在许多严重的副作用。最明显的是，它们损害了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，即使不是提高了疗效，也是类似的，但毒性更低，特异性更高，不会抑制保护性免疫反应，必须暂时提供。Isgenis的技术是基于自然的否决权免疫抑制现象。Isgenis的工程否决权利用CD8 1链的表面表达将细胞转化为特异性免疫抑制实体。Isgenis认为，其否决技术将改变免疫抑制的范式，从全身性(一般)到组织特异性(组织中心)。Isgenis的科学家们利用工程抗体和不同的否决权载体(VV)在不同组织的表面安装CD8 1-链，建立了否决方法的总体可行性。在这项SBIR的第一阶段中，Isgenis确立了转导VV的小鼠肝细胞在免疫能力强的同种异体受体中免受排斥反应的保护。此外，还开发了一种新型的腺病毒基因转移载体体系。它使临床VV的设计成为一种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。对于这项SBIR的第二阶段，Isgenis建议(I)优化肝细胞转导和移植方案，(Ii)建立非人类灵长类(NHP)肝细胞移植模型，以测试临床VVS的功能、药理和毒性。随着该项目完成产品开发的临床前阶段，将收集提交研究新药(IND)申请所需的数据，用于移植经否决工程处理的同种异体人肝细胞。已经开始与食品和药物管理局(FDA)讨论VVS及其在移植中的使用。Isgenis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，以执行计划中的研究。 公共卫生相关性：肝和肝细胞移植已经成功地用于患有不同获得性和遗传性肝病的患者。一般的免疫抑制方案已被用于保护同种异体肝组织免受排斥反应。尽管取得了成功，但它们也存在许多严重的副作用。最明显的是，它们损害了免疫系统的保护功能。Isgenis一直在开发保护同种异体移植物的新疗法，这些疗法即使没有提高疗效，也具有类似的疗效，但毒性更低，特异性更高，不会抑制保护性免疫反应，最多只能暂时提供。

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.