Adeno-Associated Virus Serotype 8 Gene Transfer Rescues a Neonatal Lethal Murine Model of Propionic Acidemia
- 1 April 2011
- journal article
- research article
- Published by Mary Ann Liebert Inc in Human Gene Therapy
- Vol. 22 (4), 477-481
- https://doi.org/10.1089/hum.2010.164
Abstract
Propionic acidemia (PA) is an autosomal recessive disorder of metabolism caused by a deficiency of propionyl-coenzyme A carboxylase (PCC). Despite optimal dietary and cofactor therapy, PA patients still suffer from lethal metabolic instability and experience multisystemic complications. A murine model of PA (Pcca–/–) of animals that uniformly die within the first 48 hr of life was used to determine the efficacy of adeno-associated viral (AAV) gene transfer as a potential therapy for PA. An AAV serotype 8 (AAV8) vector was engineered to express the human PCCA cDNA and delivered to newborn mice via an intrahepatic injection. Greater than 64% of the Pcca–/– mice were rescued after AAV8-mediated gene transfer and survived until day of life 16 or beyond. Western analysis of liver extracts showed that PCC was completely absent from Pcca–/– mice but was restored to greater than wild-type levels after AAV gene therapy. The treated Pcca–/– mice also exhibited markedly reduced plasma levels of 2-methylcitrate compared with the untreated Pcca–/– mice, which indicates significant PCC enzymatic activity was provided by gene transfer. At the time of this report, the oldest treated Pcca–/– mice are over 6 months of age. In summary, AAV gene delivery of PCCA effectively rescues Pcca–/– mice from neonatal lethality and substantially ameliorates metabolic markers of the disease. These experiments demonstrate a gene transfer approach using AAV8 that might be used as a treatment for PA, a devastating and often lethal disorder desperately in need of new therapeutic options.Keywords
This publication has 20 references indexed in Scilit:
- Liver-Directed Recombinant Adeno-Associated Viral Gene Delivery Rescues a Lethal Mouse Model of Methylmalonic Acidemia and Provides Long-Term Phenotypic CorrectionHuman Gene Therapy, 2010
- Long-term Rescue of a Lethal Murine Model of Methylmalonic Acidemia Using Adeno associated Viral Gene TherapyMolecular Therapy, 2010
- Short-Term Rescue of Neonatal Lethality in a Mouse Model of Propionic Acidemia by Gene TherapyHuman Gene Therapy, 2009
- Clinical, pathological, and biochemical studies in a patient with propionic acidemia and fatal cardiomyopathyMolecular Genetics and Metabolism, 2005
- Potential relationship between genotype and clinical outcome in propionic acidaemia patientsEuropean Journal of Human Genetics, 2000
- Clinical outcome and long-term management of 17 patients with propionic acidaemiaEuropean Journal of Pediatrics, 1996
- Acute Basal Ganglia Infarction in Propionic AcidemiaJournal of Child Neurology, 1995
- Pancreatitis in patients with organic acidemiasThe Journal of Pediatrics, 1994
- Cardiomyopathy in propionic acidaemiaEuropean Journal of Pediatrics, 1993
- L-carnitine enhances excretion of propionyl coenzyme A as propionylcarnitine in propionic acidemia.JCI Insight, 1984