Targeted gene therapy for rat glomerulonephritis using HVJ‐immunoliposomes

Abstract

Kidney targeted gene transfer has been attempted by many researchers over the last 10 years; however, unfortunately, no reliable technique for gene transfer to the kidney has been established. At experimental level several in vivo gene transfer methods have been reported. We were the first to report successful in vivo gene transfer into the kidney using the HVJ-liposome method. Since then, this method has been modified to achieve highly efficient gene transfer. In this study, we have developed a renal glomerulus-specific gene transfer method using HVJ-liposomes with anti-Thy 1 antibody, OX-7. Following systemic delivery of fluoroisothiocyanate (FITC)-labeled oligodeoxynucleotides (ODN) by HVJ-liposomes coupled with OX-7, we observed fluorescence in renal glomeruli from 2 h post-administration. To examine the efficacy of this delivery system, NF-kappaB or scrambled (SD) decoy ODN was administered by HVJ-liposomes coupled with OX-7 into a crescent glomerulonephritis, anti-glomerular basement membrane (GBM) model. Animals given SD decoy ODN developed severe glomerulonephritis by day 7 with heavy albuminuria, glomerular crescent formation and up-regulated renal expression of IL-1beta and ICAM-1. In contrast, NF-kappaB decoy ODN treatment substantially inhibited the disease with a reduction in alubuminuria, histological damage and the renal expression of inflammatory cytokines. This study has demonstrated that systemic delivery of HVJ-liposomes coupled with OX-7 results in efficient ODN transfer in rat glomeruli. NF-kappaB, but not SD decoy ODN administered systemically via HVJ-liposomes complexed with OX-7 showed clear therapeutic potential for glomerulonephritis. This novel ODN transfer method combined with decoy strategy has the potential to lead to the establishment of a new therapeutic approach to glomerular diseases.