Gene therapy with neurogenin3, betacellulin and SOCS1 reverses diabetes in NOD mice.
Gene therapy with neurogenin3, betacellulin and SOCS1 reverses diabetes in NOD mice.
复制标题
使用神经原素 3、β细胞素和 SOCS1 进行基因治疗可逆转 NOD 小鼠的糖尿病。
作者：
Li,R;Buras,E;Lee,J;Liu,R;Liu,V;Espiritu,C;Ozer,K;Thompson,B;Nally,L;Yuan,G;Oka,K;Chang,B;Samson,S;Yechoor,V;Chan,L
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 non-obese diabetic (NOD) diabetic mice, a model of autoimmune diabetes. We demonstrate that gene therapy with helper-dependent adenovirus carrying neurogenin3 (Ngn3), an islet lineage-defining transcription factor, and betacellulin (Btc), 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 Ngn3 and Btc. 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.
