Adeno-associated viruses (AAVs) are naturally defective human parvoviruses that are being developed as delivery systems (vectors) for gene therapies to treat diabetes and many other chronic diseases. Pancreatic islet transplantation has shown some modest success in the treatment of type 1 diabetes. Progress has been hindered by several factors. First, transplanted islets are recognized as foreign and are rejected by the immune system. Second, the autoimmune response that killed the recipients original islets, causing the original type 1 diabetes, can destroy the donor islets. To get around these problems, patients are treated with drugs to repress the immune system. Many of these drugs have such severe side-effects that their long-term use is not tolerable for many patients. We and others have hypothesized that the introduction of genes encoding proteins that locally suppress the immune system may protect the islets while minimizing the side effects associated with systemic immune suppression. We previously demonstrated that a recombinant AAV2 vector packaged in an AAV5 capsid (AAV2/5) could transduce approximately 10% of rat pancreatic islet cells in vitro and that this transduction did not alter islet function in vitro, or in vivo, when these islets were transplanted into diabetic, immune-deficient mice. We next proceeded to determine if rat islets transduced with an AAV2/5 vector containing the immunosuppressive transforming growth factor-beta 1 (TGF-beta 1) gene were protected from immune attack when transplanted into immune-competent diabetic mice. Such an experiment is complicated by the fact that in non-dividing cells, it takes about 1 month for genes within an AAV vector to be expressed fully. We therefore had to treat the mice with the immunosuppressant drugs sirolimus and tacrolimus for the first month after transplantation. Forty days after the immunosuppressive drugs were stopped, nearly all the mice were diabetic and there was no significant difference between mice that received transduced versus untransduced islets. Given that TGF-beta 1 has shown a positive effect on transplanted islet survival when delivered by other means, the simplest explanation is that we are not getting sufficient expression of TGF-beta 1 with our current transduction system.
| Craig, Anthony T; Gavrilova, Oksana; Dwyer, Nancy K et al. (2009) Transduction of rat pancreatic islets with pseudotyped adeno-associated virus vectors. Virol J 6:61 |
