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Adeno-Associated Virus Serotype 8 Gene Transfer Rescues a Neonatal Lethal Murine Model of Propionic Acidemia

Year: 2010

Type: article

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. Propionic acidemia (PA) is an organic acidemia caused by mutations in either the PCCA or PCCB gene. The disease is observed primarily in neonates and presents as hyperammonemia, vomiting, p. feeding, and hypotonia and progresses into a life-threatening metabolic crisis. In this report, Chandler and colleagues demonstrate that AAV8-mediated gene delivery to Pcca−/− mice can provide long-term rescue of the neonatal lethal phenotype and significantly reduce the levels of propionyl-CoA-derived metabolites.

Source: Human Gene Therapy

DOI: 10.1089/hum.2010.164