Gene therapy shows promise in treating maple syrup urine disease

A gene replacement therapy was able to restore metabolic homeostasis and prevent perinatal death in mouse and calf models of maple syrup urine disease (MSUD), a rare disease in which the body is unable to process amino acids properly.

MSUD is a genetic disorder caused by mutations in the BCKDHA, BCKDHB and DBT genes. People with MSUD can’t break down three specific amino acids found in protein-containing foods — leucine, isoleucine and valine — which build up and become toxic. The buildup causes the telltale sign of MSUD: urine, earwax or sweat that smells like maple syrup or burnt sugar.

Researchers designed a dual-function recombinant adeno-associated virus serotype 9 (rAAV9) vector to deliver codon-optimized BCKDHA and BCKDHB (rAAV9.hA-BiP-hB) to the liver, muscle, heart and brain as treatment for MSUD. The treatment prevented perinatal death, restored holoenzyme activity and improved growth in two mouse models of MSUD. A bovine version of the construct was also administered to a calf with MSUD, resulting in normal growth and progression to an unrestricted diet.

The research, published in Science Translational Medicine, highlights the promise of a one-time BCKDHA-BCKDHB systemic dual-gene replacement strategy as a therapeutic alternative to standard treatment for MSUD, which is a prescription diet and potential liver transplant.

The research was funded in part through a sponsored research agreement with ASC Therapeutics, a California-based biopharma that uses it proprietary gene editing platform to advanced treatments of rare blood diseases. Two of the labs involved in the study received grants from the National Institutes of Health, a third lab received a grant from the Department of Defense.