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

Randy J. Chandler, Suma Chandrasekaran, Nuria Carrillo-Carrasco, Julien S. Senac, Sean E. Hofherr, Michael A. Barry, Charles P. Venditti

Research output: Contribution to journalArticle

26 Scopus citations

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 48hr 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.

Original languageEnglish (US)
Pages (from-to)477-481
Number of pages5
JournalHuman gene therapy
Volume22
Issue number4
DOIs
StatePublished - Apr 1 2011

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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    Chandler, R. J., Chandrasekaran, S., Carrillo-Carrasco, N., Senac, J. S., Hofherr, S. E., Barry, M. A., & Venditti, C. P. (2011). Adeno-associated virus serotype 8 gene transfer rescues a neonatal lethal murine model of propionic acidemia. Human gene therapy, 22(4), 477-481. https://doi.org/10.1089/hum.2010.164