Synergism of highly transducible adenovirus encoding heme oxygenase 1 gene and low-dose immunosuppressants for successful outcomes of xenotransplanted pancreatic islet

Abstract

Pancreatic islet transplantation is a promising strategy for diabetic patients. Unfortunately, host's immune cells rapidly reject transplanted islets. Cytoprotective gene therapy has been tried to protect them. However, the transduce yield of ex vivo gene delivery into islets is very rare due to the anatomical structure of them. Therefore, we newly designed an Arg-Gly-Asp (RGD) peptide-incorporated adenovirus vector expressing cytoprotective heme oxygenase-1 (HO1) gene (RGD-Adv-HO1) for effective gene therapy to islets via RGD integrin interaction between adenovirus and islet. After exposure to islets, the transduced RGD-Adv-HO1 did not affect the viability and insulin secretion of islets with higher transduction efficacy. Moreover, HO1 showed cytoprotective effect from the presence of paraquat-induced reactive oxygen species (ROS). When the transduced islets were xenotransplanted into streptozotocin-induced diabetic Balb/c mice, their survival time in vivo was significantly prolonged with curing blood glucose level, which was attributed to the stable expression of HO1. Additionally, we found that RGD-Adv-HO1 showed a good synergistic effect in xenotransplanted islets when accompanied with low dose of immunosuppressants tacrolimus and anti-CD154 monoclonal antibody. Collectively, this new combinatorial remedy of RGD-Adv-HO1 transduction with low dose of immunosuppressive agents could be an effective therapy for successful outcome of islet transplantation.