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Updated: Jul 15, 2025
Intravenous Injections in Neonatal Mice
Published on: November 11, 2014
Systemic gene therapy using an AAV44.9 vector rescues a neonatal lethal mouse model of propionic acidemia
Randy J Chandler1, Giovanni Di Pasquale2, Eun-Young Choi1
1National Human Genome Research Institute, Bethesda, MD 20892, USA.
Insights
Gene therapy using AAV44.9 vectors shows promise for propionic acidemia (PA). A single newborn dose improved survival and reduced toxic metabolites in a new PA mouse model, highlighting potential for metabolic disorder treatments.
Area of Science:
- Biochemistry
- Genetics
- Gene Therapy
Background:
- Propionic acidemia (PA) is a rare, severe metabolic disorder.
- Current treatments for PA are insufficient, necessitating novel therapeutic approaches like gene therapy.
Purpose of the Study:
- To evaluate the efficacy of AAV44.9 vectors for delivering a therapeutic PCCA transgene.
- To establish and utilize a new genome-edited mouse model for studying PA.
Main Methods:
- Generated a Pcca-/- mouse model using genome editing.
- Administered AAV44.9 PCCA vectors systemically to newborn Pcca-/- mice.
- Assessed survival rates, plasma methylcitrate levels, and transgene expression in liver and heart.
Main Results:
- AAV44.9 PCCA vector administration at 1e11 vg/pup increased survival in Pcca-/- mice.
- Treated mice showed reduced plasma methylcitrate levels.
- High PCCA transgene expression was observed in the liver and heart of treated mice.
Conclusions:
- AAV44.9 vectors demonstrate therapeutic potential for propionic acidemia.
- The Pcca-/- mouse model accurately recapitulates PA phenotypes.
- AAV44.9 vectors may be suitable for treating various metabolic disorders requiring hepato-cardiac gene delivery.
Abstract:
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.
