Generation of a hypomorphic model of propionic acidemia amenable to gene therapy testing.

Abstract	Propionic acidemia (PA) is a recessive genetic disease that results in an inability to metabolize certain amino acids and odd-chain fatty acids. Current treatment involves restricting consumption of these substrates or liver transplantation. Deletion of the Pcca gene in mice mimics the most severe forms of the human disease. Pcca(-) mice die within 36 hours of birth, making it difficult to test intravenous systemic therapies in them. We generated an adult hypomorphic model of PA in Pcca(-) mice using a transgene bearing an A138T mutant of the human PCCA protein. Pcca(-/-)(A138T) mice have 2% of wild-type PCC activity, survive to adulthood, and have elevations in propionyl-carnitine, methylcitrate, glycine, alanine, lysine, ammonia, and markers associated with cardiomyopathy similar to those in patients with PA. This adult model allowed gene therapy testing by intravenous injection with adenovirus serotype 5 (Ad5) and adeno-associated virus 2/8 (AAV8) vectors. Ad5-mediated more rapid increases in PCCA protein and propionyl-CoA carboxylase (PCC) activity in the liver than AAV8 and both vectors reduced propionylcarnitine and methylcitrate levels. Phenotypic correction was transient with first generation Ad whereas AAV8-mediated long-lasting effects. These data suggest that this PA model may be a useful platform for optimizing systemic intravenous therapies for PA.
Authors	Adam J Guenzel, Sean E Hofherr, Matthew Hillestad, Mary Barry, Eric Weaver, Sarah Venezia, Jan P Kraus, Dietrich Matern, Michael A Barry
Journal	Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 21 Issue 7 Pg. 1316-23 (Jul 2013) ISSN: 1525-0024 [Electronic] United States
PMID	23648696 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Methylmalonyl-CoA Decarboxylase
Topics	Animals Dependovirus (genetics) Disease Models, Animal Genetic Therapy (methods) Humans Methylmalonyl-CoA Decarboxylase (genetics, metabolism) Mice Mice, Knockout Mice, Transgenic Propionic Acidemia (therapy)

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