Protection of Hepatocyte Transplants by Engineered Veto

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.