Efficacy of Adeno-associated Viral Gene Therapy as a Treatment for Methylmalonic and Propionic Acidemia.

摘要

Methylmalonic acidemia (MMA) and propionic acidemia (PA) are severe inherited metabolic disorders that have acute and chronic medical complications, which can be fatal despite medical-management with dietary restriction and co-factor supplementation. New treatments are needed for patients who do not respond to current therapies. Research has demonstrated that adenoviral mediated gene delivery can rescue neonatal lethal murine models of MMA and PA. However, the rescue of these models was short-lived, indicating a need to employ a gene transfer vector that is capable of sustained transgene expression before viral mediate gene transfer can advance to clinical trials. Recombinant adeno-associated virus (rAAV) is a gene transfer vector that can provide sustained expression in small and in large animal models including non-human primates as well as in humans without vector toxicity. For these reasons, rAAV was delivered to the murine models of MMA and PA to test the efficacy of this vector. The data presented in this dissertation show that rAAV gene delivery results in a long-term increase in enzymatic activity and decrease in disease related metabolites, and protects against fatal metabolic decompensations in murine models of MMA and PA. Ubiquitous and liver-specific transgene expression following rAAV gene transfer were equally effective at rescuing the murine model of MMA indicating that the liver is an important target for gene and cell therapies for MMA and that the use of liver transplantation as a method of cell therapy may be beneficial but not curative for patient's with MMA. In addition to showing that the correction of even a low percentage of hepatocytes can provide metabolic stability in the murine model of MMA, these gene transfer experiments demonstrate the potential of liver-directed cell therapy. Most importantly, the experiments described in this dissertation, for the first time, prove the pre-clinical efficacy of rAAV gene delivery as a therapy for MMA and PA using established murine models; the results strongly support advancing rAAV gene transfer as a treatment for patients. Furthermore, demonstrating the efficacy of gene delivery for both MMA and PA suggests that this approach can be applied to other organic acidemias, which like MMA and PA, can be non-responsive to current therapies and are in need of alternative therapies.