Remission in models of type 1 diabetes by gene therapy using a single-chain insulin analogue

A cure for diabetes has long been sought using several different approaches , including islet transplantation, regeneration of beta cells and insulin g ene therapy(1). However, permanent remission of type 1 diabetes has not yet been satisfactorily achieved. The development of type 1 diabetes results f rom the almost total destruction of insulin-producing pancreatic beta cells by autoimmune responses specific to beta cells(2-6). Standard insulin ther apy may not maintain blood glucose concentrations within the relatively nar row range that occurs in the presence of normal pancreatic beta cells(7). W e used a recombinant adeno-associated virus (rAAV) that expresses a single- chain insulin analogue (SIA), which possesses biologically active insulin a ctivity without enzymatic conversion, under the control of hepatocyte-speci fic L-type pyruvate kinase (LPK) promoter, which regulates SIA expression i n response to blood glucose levels. Here we show that SIA produced from the gene construct rAAV-LPK-SIA caused remission of diabetes in streptozotocin -induced diabetic rats and autoimmune diabetic mice for a prolonged time wi thout any apparent side effects. This new SIA gene therapy may have potenti al therapeutic value for the cure of autoimmune diabetes in humans.