Adeno-associated virus serotype 8 gene transfer rescues a neonatal lethal murine model of propionic acidemia

Hum Gene Ther. 2011 Apr;22(4):477-81. doi: 10.1089/hum.2010.164. Epub 2011 Feb 16.


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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Citrates / blood
  • Dependovirus* / genetics
  • Disease Models, Animal
  • Gene Transfer Techniques
  • Genetic Therapy*
  • Genetic Vectors* / genetics
  • Methylmalonyl-CoA Decarboxylase / genetics
  • Methylmalonyl-CoA Decarboxylase / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phenotype
  • Propionic Acidemia / therapy*
  • Survival Analysis


  • Citrates
  • 2-methylcitric acid
  • Methylmalonyl-CoA Decarboxylase