567. Prevention of Bilirubin Toxicity in the Gunn Rat by Long-Term Correction of Hyperbilirubinemia with Liver-Specific Plasmid-Based Gene Transfer

Abstract

Background: We have previously demonstrated short-term correction of hyperbilirubinemia in the Gunn rat (GR), animal model of Crigler-Najjar Disease Type I, by hepatic venous delivery of naked plasmid (pDNA) expressing human bilirubin glucuronosyl transferase (hUGT1A1) under CMV promoter. Recently, long-term expression of coagulation factors in mouse liver was reported after tail vein injection of pDNA containing alpha-1 antitrypsin promoter along with other liver-specific elements, limited only by development of antibodies to some secreted proteins. In this study we investigated whether liver-specific regulatory sequences prolong expression of hUGT1A1 in the GR, whether immune response develops to this intracellular enzyme, and whether with this approach sufficiently low bilirubin levels can be maintained to prevent renal tubular damage, the principal manifestation of chronic bilirubin toxicity in GR.