Gene therapy for the treatment of propionic acidemia.

摘要

Propionic acidemia is an organic acidemia that results from mutations in the PCCA or PCCB genes responsible for the two protein subunits of the propionyl-CoA carboxylase enzyme. Patients with PA have several metabolic abnormalities including elevated levels of glycine, propionylcarnitine, and methyl citrate. They also experience growth delay, developmental delay, and pathologies involving the brain, heart, pancreas, eyes, and muscles. The only viable treatment options for PA are protein restriction via a formula diet or liver transplantation, but neither of these treatments result in cures. To study the possible benefit of gene therapy for the treatment of PA we generated a mouse model of PA by introducing a hypomorphic human transgene with an A138T mutation onto a Pcca null mouse background. The resulting Pcca-/-(A138T) mice recapitulated many characteristics of PA in humans, and showed similar growth delay and biochemical perturbations. These mice were then used to study the utility of adeno-associated virus (AAV) serotype 8 and adenovirus serotype 5 expressing human PCCA. Both vectors mediated significant reductions in PA metabolite levels. Efficacy lasted for approximately 2 months in adenoviral treated mice but persisted for 1.5 years in male mice treated with AAV vector with expression remaining in the liver, heart, and skeletal muscle. Further studies examined the effect of tissue-specific treatments using alternate AAV serotypes and transcriptional regulation. When PCCA expression was restricted to the liver or muscle of treated mice metabolite levels were significantly lower in both indicating that there was likely a significant amount of these metabolites being produced within the muscle. Together these data provide evidence that PA disease is amenable to treatment with gene therapy and AAV vectors are able to mediate a significant degree of correction over long periods of time in mice. Additionally, the optimal treatment for individuals with PA will include correction of PCC activity in liver and muscle at a minimum to decrease the amount of PA metabolites such as methyl citrate being produced in these tissues. These studies also provide previously unknown insight into the molecular basis of the disease.