Venditti, Charles (NHGRI)
Manoli, Eirini (Irini) (NHGRI)
- In vitro data available
- In vivo data available (animal)
Methylmalonic Acidemia (MMA) is a metabolic disorder affecting 1 in 25,000 to 48,000 individuals globally. MMA is characterized by increased acidity in the blood and tissues due to toxic accumulation of protein and fat by-products resulting in seizures, strokes, and chronic kidney failure. About 60% of MMA cases stem from mutations in the methylmalonyl CoA mutase (MUT) gene encoding a key enzyme required to break down amino acids and lipids. Previous efforts to develop mice with null mutations in MUT have been unsuccessful, as such mutations result in neonatal death.
The inventors have developed the first transgenic mouse model available for the long-term study of Mut deficiency, in which low level liver-specific expression of the MUT enzyme confers rescue from neonatal lethality and replicates induction of the severe renal symptoms consistent with human MMA. This model could serve as a valuable research tool for designing treatments for MMA renal disease or a platform for pre-clinical toxicology screening of compounds with potential renal side effects.
- Model for examining renoprotective antioxidants or treatments for kidney failure resulting from drug toxicity, mitochondrial dysfunction, environmental exposure, or aging.
- Used in investigating renoprotective effects of nutritional supplements from drugs known to cause kidney damage.
- Used in discovery of MMA biomarkers.
- The model system provides a relatively non-invasive means of assessing the efficacy of renal-targeted therapies of all classes and biological types (gene therapy, small molecules, nutritional supplements, repurposed drugs).