Safe Gene Therapy for Type 1 Diabetes

Abstract : In light of accumulating evidence that the endocrine pancreas has regenerative properties, that hematopoietic chimerism can abrogate destruction of beta cells in autoimmune diabetes, and that in this way physiologically-sufficient endogenous insulin production can be restored in clinically-diabetic NOD mice, recapitulating what has also been sporadically seen in humans, we originally proposed to test reliable and clinically translatable alternatives able to re-establish euglycemia in diabetic patients. Instead of relying on the risky allogeneic BM transplantation to obliterate the autoimmune process that causes type 1 diabetes, we originally proposed to reconstitute, by gene supplantation, susceptible (non-Asp57+) NOD mice with their own BM genetically engineered ex vivo to also express a resistance (Asp57+) MHC class II molecule. The thymus of the reconstituted mice -- carrying BM-derived cells that co-expressed both their own diabetogenic (non-Asp57) and the transfected Asp57 beta chain -- repopulated by the engineered BM cells, can restore an efficient negative selection and consequently the ability to delete T cells potentially auto-reactive to pancreatic beta cells. These diabetics will then be disease-free.