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 >200 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.
Thesaurus Terms: 1h-Thieno(3,4-D)Imidazole-4-Pentanoic Acid, Hexahydro-2-Oxo-, (3as-(3aalpha,4beta,6aalpha))-;2-Deoxy-2-((Methylnitrosoamino)Carbonyl)Amino-D-Glucose;2-Deoxy-2-(3-Methyl-3-Nitrosoureido)-D-Glucopyranose;2-Deoxy-2-[[(Methylnitrosamino)-Carbonyl]amino]-D-Glucopyranose;Apo-1 Antigen;Apo-1 Cell Surface Antigen;Acute;Alloantigen;Allogenic;Animals;Apoptosis;Apoptosis Antigen 1;Apoptosis Antigen Ligand 1;Apoptosis Pathway;Apoptotic;Architecture;Au Element;Autoantigens;Autologous Antigens;Autoregulation;B9 Endocrine Pancreas;Biotin;Cd178 Antigen;Cd95 Antigens;Cd95 Ligand;Cd95 Antigen Ligand;Cd95 Molecule;Cell Death, Programmed;Cell Growth And Maintenance;Cell Maintenance;Cell Surface;Cells;Chimera Protein;Chimeric Proteins;Chronic;Clinic;Clinical;Clinical Treatment;Clinical Trials;Clinical Trials, Therapy;Clinical Trials, Unspecified;Critiques;Data;Diabetes Mellitus;Diabetes Mellitus, Brittle;Diabetes Mellitus, Insulin-Dependent;Diabetes Mellitus, Juvenile-Onset;Diabetes Mellitus, Ketosis-Prone;Diabetes Mellitus, Sudden-Onset;Diabetes Mellitus, Type 1;Diabetes Mellitus, Type I;Disease;Disorder;Drugs;Effector Cell;Engineering;Engineering / Architecture;Engineerings;Event;External Domain;Extracellular Domain;Face;Fas Ligand;Fas Ligand (Fasl);Fas-L;Fasl Protein;Figs;Figs - Dietary;Freedom;Fusion Protein;Generations;Gold;Graft Rejection;Graft Survival;Grafting, Islets Of Langerhans;Grant;Harvest;Homeostasis;Human;Human, General;Humulin R;Idd;Iddm;Itx;Immune;Immune Tolerance;Immunologic Tolerance;Immunologically Directed Therapy;Immunomodulation;Immunosuppressants;Immunosuppression Effect;Immunosuppressions (Physiology);Immunosuppressive Agents;Immunosuppressive Effect;Immunotherapeutic Agent;Immunotherapy;Implant;Individual;Insulin;Insulin (Ox), 8a-L-Threonine-10a-L-Isoleucine-30b-L-Threonine-;Insulin, Regular;Insulin-Dependent Diabetes Mellitus;Islands Of Langerhans;Islet Cell;Islet Cells;Islets Of Langerhans;Islets Of Langerhans Transplantation;Lead;Liberty;Licensing;Lymphocyte;Lymphocytic;Macaca;Macaca Mulatta;Macaque;Mammals, Mice;Mammals, Primates;Mammals, Rodents;Man (Taxonomy);Man, Modern;Medication;Metabolic;Mice;Modeling;Modification;Murine;Mus;Natural Immunosuppression;Nesidioblasts;Novolin R;Outcome;Pancreas, Endocrine;Pancreatic Islets;Pars Endocrina Pancreatis;Pb Element;Peripheral;Pharmaceutic Preparations;Pharmaceutical Agent;Pharmaceutical Preparations;Pharmaceuticals;Pharmacologic Substance;Pharmacological Substance;Phase;Physiological Homeostasis;Physiology;Play;Pre-Clinical Model;Preclinical Models;Prevention;Primates;Procedures;Proteins;Protocol;Protocols Documentation;Publishing;Qol;Quality Of Life;Rapamune;Rapamycin;Recovery;Regulatory T-Lymphocyte;Replacement Therapy;Rhesus;Rhesus Macaque;Rhesus Monkey;Rodent;Rodent Model;Rodentia;Rodentias;Role;Sbir;Sbirs (R43/44);Stz;Self-Antigens;Series;Sirolimus;Small Business Innovation Research;Small Business Innovation Research Grant;Strepavidin;Streptavidin;Streptozocin;Streptozotocin;Surface;T-Cells;T-Lymphocyte;T1 Diabetes;T1d;T1dm;Tnfrsf6 Receptor;Technology;Testing;Therapeutic;Therapeutic Trials;Therapy Clinical Trials;Thymus-Dependent Lymphocytes;Translating;Translatings;Translations;Transplant Rejection;Transplantation;Transplantation Rejection;Transplantation, Islands Of Langerhans;Transplantation, Islands Of Pancreas;Transplantation, Islet;Transplantation, Pancreatic Islets;Treatment Efficacy;Tumor Necrosis Factor Ligand Superfamily Member 6;Tumor Necrosis Factor Receptor Superfamily, Member 6;Type 1 Diabetes;Vitamin H;Work;Zanosar;Base;Beta Cell Development;Clinical Investigation;Coenzyme R;Commercialization;Diabetes;Diabetic;Disease/Disorder;Drug/Agent;Economic Impact;Efficacy Testing;Endocrine Pancreas;Endocrine Pancreas Development;Experiment;Experimental Research;Experimental Study;Facial;Fas Antigens;Fas Receptors;Gene Product;Heavy Metal Pb;Heavy Metal Lead;Immune Modulation;Immune System Tolerance;Immune Therapy;Immune Unresponsiveness;Immunogenicity;Immunologic Preparation;Immunologic Reactivity Control;Immunological Paralysis;Immunoregulation;Immunosuppression;Immunosuppressive;Immunotherapeutics;Improved;Insulin Dependent Diabetes;Insulin Secretion;Islet;Islet Beta Cell Transplantation;Islet Cell Transplant;Islet Cell Transplantation;Islet Development;Islet Progenitor;Islet Transplantation;Juvenile Diabetes;Juvenile Diabetes Mellitus;Ketosis Prone Diabetes;Language Translation;Lymph Cell;Non-Human Primate;Nonhuman Primate;Novel;Novel Therapeutic Intervention;Public Health Relevance;Research Study;Response;Social Role;Therapeutic Efficacy;Therapeutically Effective;Thymus Derived Lymphocyte;Transplant;Trial Regimen;Trial Treatment;Type I Diabetes
