Generation of a Hypomorphic Model of Propionic Acidemia Amenable to Gene Therapy Testing
| Autor: | Mary E. Barry, Sean E. Hofherr, Matthew L. Hillestad, Eric A. Weaver, Sarah Venezia, Jan P. Kraus, Dietrich Matern, Michael A. Barry, Adam J. Guenzel |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Methylmalonyl-CoA Decarboxylase
Propionic Acidemia Genetic enhancement Transgene Mutant Mice Transgenic Biology Virus Mice 03 medical and health sciences 0302 clinical medicine Drug Discovery Genetics medicine Animals Humans Propionic acidemia Molecular Biology Gene 030304 developmental biology Mice Knockout Pharmacology chemistry.chemical_classification 0303 health sciences Genetic Therapy Dependovirus medicine.disease Molecular biology 3. Good health Amino acid Disease Models Animal Biochemistry chemistry Glycine Molecular Medicine Original Article 030217 neurology & neurosurgery |
| Zdroj: | Molecular Therapy. 21:1316-1323 |
| ISSN: | 1525-0016 |
| DOI: | 10.1038/mt.2013.68 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|