Gene therapy with neurogenin3, betacellulin and SOCS1 reverses diabetes in NOD mice

Islet transplantation for Type 1 diabetes is limited by a shortage of donor islets and requirement for immunosuppression. We approached this problem by inducing in vivo islet neogenesis in NOD diabetic mice, a model of autoimmune diabetes. We demonstrate that gene therapy with helper-dependent adenovirus (HDAd) carrying neurogenin3, an islet lineage-defining transcription factor and betacellulin, an islet growth factor, leads to the induction of periportal insulin-positive cell clusters in the liver, which are rapidly destroyed. To specifically accord protection to these ‘neo-islets’ from cytokine-mediated destruction, we overexpressed suppressor of cytokine signaling 1 (SOCS1) gene, using a rat insulin promoter in combination with neurogenin3 and betacellulin. With this approach, about half of diabetic mice attained euglycemia sustained for over 4 months, regain glucose tolerance and appropriate glucose-stimulated insulin secretion. Histological analysis revealed periportal islet hormone-expressing ‘neo-islets’ in treated mouse livers. Despite evidence of persistent ‘insulitis’ with activated T-cells, these ‘neo-islets’ persist to maintain euglycemia. This therapy does not affect diabetogenicity of splenocytes, as they retain the ability to transfer diabetes. This study thus provides a proof-of-concept for engineering in vivo islet neogenesis with targeted resistance to cytokine-mediated destruction to provide a long-term reversal of diabetes in NOD mice.