Widespread and Stable Pancreatic Gene Transfer by Adeno-Associated Virus Vectors via Different Routes

Abstract

Diabetes is a disease of epidemic proportions and is

DsAAV8-mediated expression of glucagon-like peptide-1 in pancreatic beta-cells ameliorates streptozotocin-induced diabetes

“…28 Expression can be further restricted within the islet by coupling transgene expression to activation of the MIP, 28 thereby providing an opportunity to specifically target the expression of therapeutic genes within beta-cells. AAV vectors represent an innovative gene therapy tool, having reduced immunogenicity compared with that of adenoviruses, 36 while being capable of directing long-term expression of transgenes both in humans and in mice.…”

“…33 The observation that the majority of GLP-1-positive beta-cells are located in the periphery of the islet, is consistent with the intraperitoneal delivery route and has been observed previously for DsAAV8-mediated transgene expression in islets. 28 To investigate the mechanisms contributing to improved glucose tolerance in mice receiving DsAAV8-MIP-GLP-1, a pancreatic morphometric analysis was performed. Animals expressing beta-cell GLP-1 had similar total insulin-positive area (0.0033 ± 0.0004 in GLP-1-treated animals versus 0.0026 ± 0.0007 in control animals), but trended toward an increase in the total number of insulin-positive areas per mm 2 of pancreatic tissue (15.9 ± 1.5 versus 11.4 ± 1.9 in control animals; P ¼ 0.097) due to significant increase in the number of small insulin-positive clusters (Figures 5a and b).…”

“…Several different AAV serotypes have now been identified, 26 with serotype-8 exhibiting an ability to efficiently transduce pancreatic tissue. 27,28 Wang et al 28 have recently shown that in vivo administration of AAV8 vectors containing enhanced greenfluorescent protein (eGFP) driven by the mouse insulin-II promoter (MIP) results in efficient transduction of pancreatic beta-cells. Furthermore, it has been shown that therapeutic genes can be delivered to beta-cells through intraperitoneal injection of AAV8.…”

Transgene and islet cell delivery systems using nano-sized carriers for the treatment of diabetes mellitus

“…Fibroblast growth factor receptor, αvβ5 integrin, and hepatocyte growth factor receptor have been reported to work as co-factors [36–38]. Among the many types of AAV, single-stranded AAV, such as serotypes 8 (AAV-8) and 9 (AAV-9), and double-stranded AAV have been reported to have effective transduction of transgenes into the pancreas [39–44]. …”

“…In terms of administration routes of viral vectors for the delivery of transgenes to the pancreas in vivo , although intravenous administration has been used most often, intrapancreatic ductal injections might be more efficient because transgenes with viral vectors can more easily escape from phagocytes in the liver via this administration route [51]. The transduction efficiency of transgenes with viral vectors in the pancreas via intravenous administration was reported to improve under conditions of reduced blood flow to the liver, such as with a liver bypass or transient blockade of liver circulation [44,52]. However, other studies have reported that intravenous administration of AAV-8 or AAV-9 substantially delivered transgenes to the pancreas [40,53].…”