Novel Adeno-associated Viral (AAV) Vectors to Treat Hereditary Methylmalonic Acidemia (MMA) Caused by Methylmalonyl-coA Mutase (MMUT) Deficiency

Deficiency of the enzyme in methylmalonyl-CoA mutase (MMUT) results is a life-threatening disease, methylmalonic acidemia (MMA), that carries high rates of morbidity and mortality. NHGRI scientists have developed novel AAV vectors that combine the proprietary codon-optimized synMMUT alleles with either a liver-specific promoter from the human alpha-1 antitrypsin (hAA T) locus to produce a vector that directs MMUT protein expression in a liver-specific fashion or the human elongation factor 1a (EF1 alpha) promoter to produce a vector that expresses the MMUT protein at moderate levels in a global fashion, including the liver. These AAV vectors have high potency in vivo, and therefore represent a class of new gene therapies that might be given to patients with MMA. The AAV constructs developed and enabled as serotype 8 or 9 vectors could be immediately translated to the clinic.