Long-term correction of hyperbilirubinemia in the Gunn rat by repeated intravenous delivery of naked plasmid DNA into muscle.

Abstract

We evaluated nonviral gene delivery into skeletal muscle via femoral artery and great saphenous vein for correction of hyperbilirubinemia in the Gunn rat, the animal model of Crigler-Najjar syndrome type I. A single injection of pDNA expressing hUGT1A1 under the CMV promoter resulted in excretion of bilirubin glucuronides in bile and a significant decrease in serum bilirubin for at least 2 or 4 weeks, respectively. Loss of metabolic effect was associated with a decrease in recombinant protein in muscle, while pDNA and transcript were detectable 4 weeks after gene delivery. Monthly intravenous gene delivery maintained metabolic correction for at least 5 months. Fibrosis around vessels in the arterial group limited the number of successful repeat gene transfer sessions to 3. Animals expressing hUGT1A1 developed anti-hUGT1A1 antibodies and lymphocytic infiltrate in muscle. Immunosuppression abrogated antibody response, ameliorated lymphocytic inflammation, and enhanced metabolic correction but did not prevent a decrease in the amount of recombinant protein. In conclusion, repeated intravenous delivery of pDNA into muscle enables long-term correction of hyperbilirubinemia in the Gunn rat. The procedure is safe and simple, with great clinical potential. Further studies are needed to explain the mechanisms of loss and improve the stability of recombinant hUGT1A1 in muscle.

• Authors: Zhen Jia, István Dankó
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 12 Issue 5 Pg. 860-6 (Nov 2005) ISSN: 1525-0016 [Print] United States
• PMID: 16019265 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ugt1a1 protein, rat
• DNA
• UGT1A1 enzyme
• Glucuronosyltransferase
• Bilirubin

Topics

• Animals
• Bilirubin (blood)
• Crigler-Najjar Syndrome (genetics, therapy)
• DNA
• Disease Models, Animal
• Gene Transfer Techniques
• Genetic Therapy
• Genetic Vectors
• Glucuronosyltransferase (biosynthesis, genetics)
• Immunosuppression Therapy
• Injections, Intravenous
• Liver (metabolism)
• Plasmids (genetics)
• Rats
• Rats, Gunn