Transplantation of human islets has great potential as an effective means of treating insulin dependent diabetes mellitus. Primary non-function is the main cause of islet graft failure and it results in the need for multi-donor transplants. We will test the hypothesis that islet engraftment can he enhanced simultaneously by expressing growth factor gene like human Vascular Endothelial Growth Factor (hVEGF) that promotes islet revascularization, and antiapoptotic gene like human interleukin-1 receptor antagonist (hIL-IRa) to prevent apoptosis of transplanted islets in the host. In preliminary studies, higher levels of hVEGF were secreted from human islets transfected with bicistronic adenoviral vector encoding hVEGF and Green Fluorescent Protein (Acv-GFP-hVEGF), while hVEGF secretion from Adv-GFP transfected and mock-transfected islets was very low. Insulin release from transfected islets was comparable to mock-transfected islets. Proapoptotic cytokines IFN-gamma and TNF-alpha did not induce apoptosis when islets were transfected with Adv-GFP-hVEGF.
Our specific aims are to determine whether i) adenoviral vectors encoding hVEGF and hIL-IRa (AdvhVEGF- hlL-lRa) will efficiently transfect islets and improve their function; and ii) ex vivo transfection with Adv-hVEGF-hlL-IRa will prevent primary islet nonfunction and reduce the islet mass needed for restoring normoglycemia. The significance of this research is that the proposed ex vivo gene therapy will promote islet revascularization, prevent apoptosis and decrease the number of islets required for achieving normoglycemia. The data will be beneficial to successful human islet transplantation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK069968-04
Application #
7418614
Study Section
Special Emphasis Panel (ZRG1-GDD (01))
Program Officer
Appel, Michael C
Project Start
2005-07-15
Project End
2009-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
4
Fiscal Year
2008
Total Cost
$238,771
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Mundra, Vaibhav; Wu, Hao; Mahato, Ram I (2013) Genetically modified human bone marrow derived mesenchymal stem cells for improving the outcome of human islet transplantation. PLoS One 8:e77591
Mundra, Vaibhav; Gerling, Ivan C; Mahato, Ram I (2013) Mesenchymal stem cell-based therapy. Mol Pharm 10:77-89
Wu, Hao; Pagadala, Jayaprakash; Yates, Charles Ryan et al. (2013) Synthesis and characterization of an anti-apoptotic immunosuppressive compound for improving the outcome of islet transplantation. Bioconjug Chem 24:2036-44
Wu, Hao; Wen, Di; Mahato, Ram I (2013) Third-party mesenchymal stem cells improved human islet transplantation in a humanized diabetic mouse model. Mol Ther 21:1778-86
Wu, Hao; Lu, Wenli; Mahato, Ram I (2011) Mesenchymal stem cells as a gene delivery vehicle for successful islet transplantation. Pharm Res 28:2098-109
Ye, Zhaoyang; Mahato, Ram I (2011) Combining stem cells and genes for effective therapeutics. Mol Pharm 8:1443-5
Wu, Hao; Yoon, A-Rum; Li, Feng et al. (2011) RGD peptide-modified adenovirus expressing hepatocyte growth factor and X-linked inhibitor of apoptosis improves islet transplantation. J Gene Med 13:658-69
Singh, Saurabh; Narang, Ajit S; Mahato, Ram I (2011) Subcellular fate and off-target effects of siRNA, shRNA, and miRNA. Pharm Res 28:2996-3015
Wu, Hao; Ye, Zhaoyang; Mahato, Ram I (2011) Genetically modified mesenchymal stem cells for improved islet transplantation. Mol Pharm 8:1458-70
Li, Feng; Mahato, Ram I (2011) RNA interference for improving the outcome of islet transplantation. Adv Drug Deliv Rev 63:47-68

Showing the most recent 10 out of 28 publications