Venditti, Charles (NHGRI)
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.
This technology enables systemic gene therapy for MMUT type MMA, the most common form of this devastating inborn error of metabolism.
The lead AAV developed and enabled as serotype 8 or 9 vectors could be immediately translated to the clinic.