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Ongoing Research Projects in Mahato's Lab

Design and Synthesis of Novel Polymer and Lipid Carriers

We are working on the Site-specific Delivery of Oligonucleotides and siRNA to Hepatocytes or Hepatic Stellate Cells for treatment of hepatitis and liver fibrosis. We have recently shown that the conjugation of triplex forming oligonucleotides to mannose-6-phosphate-bovine serum albumin (M6P-BSA) can significantly enhance TFO delivery to hepatic stellate cells and this M6P-BSA-TFO has the potential to treat liver fibrosis by inhibiting collagen synthesis (Ye et al, Biochemistry. 2005, 44(11):4466-76 and Bioconjug Chem, 2006;17(3):823-30).

We have also shown that cholesterol conjugation can significantly increase the hepatic uptake of TFO upon systemic administration in liver fibrotic rats (Cheng et al., J Pharmacol Exp Ther. 2006; 317(2):797-805). We also determined the biodistribution and pharmacokinetic profiles of TFO after systemic administration in normal and fibrotic rats (Cheng et al, Mol Pharm. 2005, 2(3): 206-17). Currently, we are also working on site-specific delivery of TFO and chemically synthesized siRNA for treating hepatitis and liver fibrosis by bioconjugation with polymers and lipids with or without a targeting ligand. 

Design and Construction of Plasmid and Adenovirus-based Gene Expression Systems

Despite tremendous progress in islet isolation, culture, and preservation, the clinical use of human islet transplantation for treating type I diabetes is limited due to post-transplantation challenges to the islets such as the failure to revascularize and immune destruction of the islet graft (Narang and Mahato, Pharmacol Rev.2006;58(2):194-243).

We are working on genetic modification of human islets prior to transplantation to prevent beta-cell death. To provide synergistic effect, we are trying to deliver more than one therapeutic genes using plasmid and adenoviral vectors. We also work on cationic lipids and polymers for gene delivery. Based on our recent findings (Mahato et al, Mol Ther. 2003, 7(1):89-100; Narang et al,Pharm Res. 2004; 21(1):15-25 and 2006,Sep Issue;  Cheng et al. Gene Ther. 2004;11(14):1105-16), we are currently working on construction and characterization of adenoviral vectors with different therapeutic genes for ex vivo infection into human and rat islets. In addition, we are also working on siRNA delivery to human and rat islets for silencing antiapoptotic genes for improving the outcome of islet transplantation.

siRNA Delivery for Treatment of Hepatitis, Liver Fibrosis and Diabetes

We are working on site-specific delivery of siRNA for treating liver fibrosis and ex vivo therapy for treating type I diabetes. We are also working on the design/construction of plasmid and adenovirus-based shRNA for treating these diseases.