Back to Search
Start Over
Sustained reduction of hyperbilirubinemia in Gunn rats after adeno-associated virus-mediated gene transfer of bilirubin UDP-glucuronosyltransferase isozyme 1A1 to skeletal muscle
- Source :
- Scopus-Elsevier
- Publication Year :
- 2012
-
Abstract
- Crigler-Najjar syndrome is an autosomal recessive disorder with severe unconjugated hyperbilirubinemia due to deficiency of bilirubin UDP-glucuronosyltransferase isozyme 1A1 (UGT1A1) encoded by the UGT1A1 gene. Current therapy relies on phototherapy to prevent life-threatening elevations of serum bilirubin levels, but liver transplantation is the only permanent treatment. Muscle-directed gene therapy has several advantages, including easy and safe access through simple intramuscular injections, and has been investigated in human clinical trials. In this study, we have investigated the efficacy of adeno-associated viral (AAV) vector-mediated muscle-directed gene therapy in the preclinical animal model of Crigler-Najjar syndrome, that is the Gunn rat. Serotype 1 AAV vector expressing rat UGT1A1 under the control of muscle-specific creatine kinase promoter was injected at a dose of 3×10(12) genome copies/kg into the muscles of Gunn rats and resulted in expression of UGT1A1 protein and functionally active enzyme in injected muscles. AAV-injected Gunn rats showed an approximately 50% reduction in serum bilirubin levels as compared with saline-treated controls, and this reduction was sustained for at least 1 year postinjection. Increased excretion of alkali-labile metabolites of bilirubin in bile and urine was detected in AAV-injected animals. High-performance liquid chromatography analysis of bile from AAV-injected Gunn rats showed a metabolite with retention time close to that of bilirubin diglucuronide. Taken together, these data show that clinically relevant and sustained reduction of serum bilirubin levels can be achieved by simple and safe intramuscular injections in Gunn rats. AAV-mediated muscle directed gene therapy has potential for the treatment of patients with Crigler-Najjar syndrome type 1.
- Subjects :
- Bilirubin
Genetic enhancement
Genetic Vectors
Rats, Gunn
Pharmacology
medicine.disease_cause
digestive system
Isozyme
Injections, Intramuscular
chemistry.chemical_compound
Transduction, Genetic
Genetics
medicine
Animals
Bile
Humans
Tissue Distribution
Glucuronosyltransferase
Muscle, Skeletal
Molecular Biology
Adeno-associated virus
Chromatography, High Pressure Liquid
Unconjugated hyperbilirubinemia
Hyperbilirubinemia
biology
Gene Transfer Techniques
Skeletal muscle
Genetic Therapy
Dependovirus
Gunn rat
Rats
Isoenzymes
medicine.anatomical_structure
chemistry
Biochemistry
biology.protein
Molecular Medicine
Creatine kinase
Subjects
Details
- ISSN :
- 15577422
- Volume :
- 23
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Human gene therapy
- Accession number :
- edsair.doi.dedup.....722321e69246dcc38cb4929711e5fb92