TY - JOUR
T1 - Biochemical correction of very long-chain acyl-coa dehydrogenase deficiency following adeno-associated virus gene therapy
AU - Merritt, J. Lawrence
AU - Nguyen, Tien
AU - Daniels, Jan
AU - Matern, Dietrich
AU - Schowalter, David B.
N1 - Funding Information:
This article is dedicated to the memory of David B. Schowalter (1960–2007). The authors have no financial conflicts of interest to declare. We thank Steven J. Russell, Jill M. Thompson, and the Molecular Medicine Program at the Mayo Clinic College of Medicine (Rochester, MN). We are also indebted to James M. Wilson (University of Pennsylvania, Philadelphia, PA) for providing the recombinant AAV2/8 replication plasmid and Philip A. Wood (University of Alabama, Birmingham, AL) for providing VLCAD-knockout mice. This study was supported by funding from the American Heart Association (0234938N) and Mayo Clinic College of Medicine clinical research funds.
PY - 2009
Y1 - 2009
N2 - We report the development of a gene replacement strategy for very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. VLCAD is a mitochondrial enzyme involved in fatty acid β-oxidation, a key step in energy production during times of fasting or stress. Deficiency of VLCAD classically presents as hepatic dysfunction, hypoglycemia, cardiomyopathy, rhabdomyolysis, and/or sudden death. While dietary therapy for VLCAD deficiency has proven beneficial in preventing some symptoms, a risk of metabolic catastrophic decompensation remains throughout life during times of increased energy demand. We designed a recombinant adeno-associated virus (AAV) expressing the human VLCAD gene (AAV8-hVLCAD). To demonstrate its in vivo activity, AAV8-hVLCAD was administered via the tail vein to VLCAD-knockout mice. A reduction in accumulated serum long-chain acylcarnitines and increased fasting tolerance judged on blood glucose concentrations were observed as of 11 days postinjections through >100 days. Western analysis of liver, skeletal muscle, and heart extracts using PEP1 anti-hVLCAD antibody revealed short-term hVLCAD expression in the liver and muscle and longer-term expression in heart. This demonstrates the ability of human VLCAD to correct the biochemical phenotype of VLCAD-deficient mice.
AB - We report the development of a gene replacement strategy for very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. VLCAD is a mitochondrial enzyme involved in fatty acid β-oxidation, a key step in energy production during times of fasting or stress. Deficiency of VLCAD classically presents as hepatic dysfunction, hypoglycemia, cardiomyopathy, rhabdomyolysis, and/or sudden death. While dietary therapy for VLCAD deficiency has proven beneficial in preventing some symptoms, a risk of metabolic catastrophic decompensation remains throughout life during times of increased energy demand. We designed a recombinant adeno-associated virus (AAV) expressing the human VLCAD gene (AAV8-hVLCAD). To demonstrate its in vivo activity, AAV8-hVLCAD was administered via the tail vein to VLCAD-knockout mice. A reduction in accumulated serum long-chain acylcarnitines and increased fasting tolerance judged on blood glucose concentrations were observed as of 11 days postinjections through >100 days. Western analysis of liver, skeletal muscle, and heart extracts using PEP1 anti-hVLCAD antibody revealed short-term hVLCAD expression in the liver and muscle and longer-term expression in heart. This demonstrates the ability of human VLCAD to correct the biochemical phenotype of VLCAD-deficient mice.
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U2 - 10.1038/mt.2008.295
DO - 10.1038/mt.2008.295
M3 - Article
C2 - 19156135
AN - SCOPUS:61649125586
SN - 1525-0016
VL - 17
SP - 425
EP - 429
JO - Molecular Therapy
JF - Molecular Therapy
IS - 3
ER -