Systemic gene therapy using an AAV44.9 vector rescues a neonatal lethal mouse model of propionic acidemia

Propionic acidemia (PA) is rare autosomal recessive metabolic disorder caused by defects in the mitochondrially localized enzyme propionyl-coenzyme A (CoA) carboxylase. Patients with PA can suffer from lethal metabolic decompensation and cardiomyopathy despite current medical management, which has l...

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Veröffentlicht in:Molecular therapy. Methods & clinical development 2023-09, Vol.30, p.181-190
Hauptverfasser: Chandler, Randy J., Di Pasquale, Giovanni, Choi, Eun-Young, Chang, David, Smith, Stephanie N., Sloan, Jennifer L., Hoffmann, Victoria, Li, Lina, Chiorini, John A., Venditti, Charles P.
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Sprache:eng
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Zusammenfassung:Propionic acidemia (PA) is rare autosomal recessive metabolic disorder caused by defects in the mitochondrially localized enzyme propionyl-coenzyme A (CoA) carboxylase. Patients with PA can suffer from lethal metabolic decompensation and cardiomyopathy despite current medical management, which has led to the pursuit of gene therapy as a new treatment option for patients. Here we assess the therapeutic efficacy of a recently described adeno-associated virus (AAV) capsid, AAV44.9, to deliver a therapeutic PCCA transgene in a new mouse model of propionyl-CoA carboxylase α (PCCA) deficiency generated by genome editing. Pcca−/− mice recapitulate the severe neonatal presentation of PA and manifest uniform neonatal lethality, absent PCCA expression, and increased 2-methylcitrate. A single injection of the AAV44.9 PCCA vector in the immediate newborn period, systemically delivered at a dose of 1e11 vector genome (vg)/pup but not 1e10 vg/pup, increased survival, reduced plasma methylcitrate, and resulted in high levels of transgene expression in the liver and heart in treated Pcca−/− mice. Our studies not only establish a versatile and accurate new mouse model of PA but further demonstrate that the AAV44.9 vectors may be suitable for treatment of many metabolic disorders where hepato-cardiac transduction following systemic delivery is desired, such as PA, and, by extension, fatty acid oxidation defects and glycogen storage disorders. [Display omitted] Venditti and colleagues use the AAV44.9 vector to treat a severe murine model of propionic acidemia, a lethal metabolic disorder. The AAV44.9 capsid effectively delivered a PCCA transgene to the liver and heart. AAV44.9 could be applicable to other diseases where hepatic and cardiac gene delivery are required.
ISSN:2329-0501
2329-0501
DOI:10.1016/j.omtm.2023.06.008