Hepatocyte growth factor gene therapy for islet transplantation

Abstract

Recent clinical studies have documented that human islet transplantation has the potential to replace pancreatic endocrine function in patients with type 1 diabetes. These studies have also highlighted an enormous shortage of human islets that impedes the use of islet transplantation in clinical practice on a larger scale. To address this problem, one potential approach is to use islet growth factors to increase beta cell replication, to improve beta cell function and to enhance beta cell survival. In that context, transgenic mice overexpressing hepatocyte growth factor (HGF) in the pancreatic beta cell display increased beta cell proliferation, function and survival. More importantly, HGF-overexpressing transgenic mouse islets markedly improve transplant performance in severe combined immunodeficiency (SCID) mice and reduce the number of islets required for successful islet transplantation. Recently, adenoviral-mediated gene transfer of HGF into normal rodent islets has confirmed the beneficial effects of HGF in improving islet transplant outcomes in two marginal mass islet transplant models in rodents: islet transplant under the kidney capsule in SCID mice; and portal islet allograft transplantation in rats treated with the Edmonton immunosuppressive regimen. These studies suggest that ex vivo HGF gene therapy has the potential to reduce the number of human islets required for successful islet transplantation.