Protection of Hepaticyte 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 acquired a nd genetic 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 at best 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 ?- chain to transform cells and 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). Isogenis now proposes to examine whether hepatocytes can be transduced with VVs and can be permanently protected from rejectio n in allogeneic hosts. Hepatocyte transplantation may represent the ideal model. Hepatocytes are of low immunogenicity, they can be manipulated ex vivo with relative ease and in most cases their engraftment is not complicated by underlying autoimmune disea se processes. Isogenis will lay the foundation for a future Phase II SBIR grant, in which Isogenis will use a nonhuman primate model to test the functionality, pharmacology and toxicity of a clinical VV and thus will aim to complete the pre-clinical trial stage of hepatocyte transplantation. Discussions with the Food and Drug Administration (FDA) about VVs and their use in transplantation have been initiated. Liver and hepatocyte transplantations have successfully been performed in patients suffering from d ifferent 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 t o be provided transiently.