ApoFasL as a novel treatment for Type 1 Diabetes in Nonhuman Primates

DESCRIPTION (provided by applicant): Pancreatic islet transplantation is a viable approach for the treatment of type 1 diabetes (T1D). However, this therapeutic approach suffers from graft rejection. Dr. Shirwan, founder of ApoImmune, has developed a novel immunotherapeutic approach aimed at tolerance induction to alloantigens without chronic use of general immunosuppression. This approach, termed ApoFasL, involves engineering pancreatic islets ex vivo using the Company's platform ProtEx(tm) technology in a rapid, practical, and nontoxic manner to efficiently display a novel form of Fas ligand (FasL) on the islet surface. Engineered islets transplanted into diabetic allogeneic mice recipients treated with a short course (15 days) of rapamycin resulted in 100% survival over an observation period of gt200 days without any sign of rejection. Moreover, since the last submission of this grant, we have now followed these animals long-term. Recipients of FasL-engineered islet grafts enjoyed rejection-free survival, unless their Treg cells were depleted. Some of these animals are over 500 (n=8) and 400 (n=12) days with functioning islets in the absence of any immunosuppression. These data demonstrate that tolerance induction is sufficient for long-term, drug free survival. Building on this and other strong data obtained in rodent models, the primary objective of this proposal is to test the efficacy of this novel therapeutic approach, ApoFasL, for tolerance induction to allogeneic pancreatic islets in rhesus macaques. FasL will be displayed on rhesus macaque donor islets using ProtEx(tm) technology prior to transplantation into chemically-induced diabetic macaques. Transplants will be done under transient cover of rapamycin, a pharmaceutical agent used in the clinic for the prevention of graft rejection. The rationale for using rapamycin in these experiments is two-fold. First, it will face fewer regulatory hurdles and ease translation of the ApoFasL protocol into the clinic. And second, it works in synergy with FasL to eliminate pathogenic T effector cells and generate/expand protective T regulatory cells, thereby enhancing ApoFasL's efficacy. We hypothesize that islets engineered to display FasL on their surface will induce tolerance by physically eliminating alloreactive pathogenic lymphocytes responding to the transplanted islets through Fas/FasL interaction. Rapamycin is expected to further augment this response by eliminating T effector cells and/or expanding T regulatory cells, thereby creating donor- specific immune tolerance, leading to the survival of transplanted islets. Proof-of-principle in a nonhuman primate model will be followed by a Phase II SBIR application to further develop ApoFasL into a lead product. Tolerance to allogeneic islets in a nonhuman primate model will serve as the first step towards translation of this novel immunotherapy to the clinic for the treatment of T1D. If proven effective, ApoFasL may improve the quality of life for millions of individuals worldwide with an economic impact in the billions of dollars. PUBLIC HEALTH RELEVANCE: ApoFasL is a novel immunotherapy being developed for the treatment of Type 1 Diabetes (T1D). Successful completion of this proposal testing ApoFasL in a diabetic nonhuman primate model will be a significant step toward developing ApoFasL for clinical trials. This novel therapy has the potential to break new grounds for the clinical treatment of T1D.