Novel Codon-Optimized Gene Therapeutic for Methylmalonic Acidemia

Methylmalonic Acidemia (MMA) is a metabolic disorder 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. A significant portion of MMA cases stem from a deficiency in a key mitochondrial enzyme, methylmalonyl-CoA mutase (MUT), required to break down amino acids and lipids. Currently, there are no treatments for MMA and the disease is managed primarily with dietary restriction of amino acid precursors and liver-kidney transplantation in severe cases.

The present invention describes a synthetic codon-optimized MUT gene (co-MUT) that improves expression of human methylmalonyl-CoA mutase. A series of novel gene therapy vectors containing co-MUT rescued MMA mice from lethality and lowered levels of methylmalonic acid in the blood. Results of pre-clinical efficacy studies demonstrate a promising therapy for MMA and other renal-associated disorders.