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  • Title: Bipartite adenoviral vector encoding hHGF and hIL-1Ra for improved human islet transplantation.
    Author: Panakanti R, Mahato RI.
    Journal: Pharm Res; 2009 Mar; 26(3):587-96. PubMed ID: 19002565.
    Abstract:
    PURPOSE: Ex vivo gene therapy can improve the outcome of islet transplantation for treating type I diabetes. Hepatocyte growth factor (HGF) increases beta-cell proliferation and promotes revascularization of islets, while interleukin-1 receptor antagonist (hIL-1Ra) inhibits islet cell apoptosis. METHODS: We constructed Adv-hHGF-hIL-1Ra by cloning hHGF and hIL-1Ra coding sequences and polyA signal under separate CMV promoters in Adenoquick plasmid. RESULTS: There was dose and time dependent expression of these genes after transduction of Adv-hHGF-hIL-1Ra into human islets. Compared to un-transduced islets, hHGF and hIL-1Ra gene expression at protein levels was more than 60 and 40 times higher at 1,000 MOI, respectively. Transduced islets were viable after incubation with the cocktail of TNF-alpha, IL-1beta and IFN-gamma, as evidenced by insulin release in response to glucose concentration. Co-expression of hHGF and hIL-1Ra led to significant decrease in caspase-3 induced by the cytokines. Compared to un-transduced islets, transduction of islets with Adv-hHGF-hIL-1Ra at 1,000 MOI prior to transplantation under the kidney capsules of streptozotocin-induced-diabetic NOD-SCID mice reduced blood glucose levels, and increased serum insulin and c-peptide levels. CONCLUSIONS: Transduction of islets with Adv-hHGF-hIL-1Ra efficiently expresses both growth factor and antiapoptotic genes, decreases caspase-3 and improves the outcome of islet transplantation.
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