A one-time injection of a novel gene therapy was able to save mice and a newborn calf from succumbing to maple syrup urine disease (MSUD), suggesting the approach could one day be used to treat patients with the rare genetic disorder.
The therapy allowed the animals to grow normally, and the treated calf was able to transition off a restricted diet that is typically required to manage the disease, according to results published in Science Translational Medicine on Feb. 26. The research team was led by scientists at the University of Massachusetts Chan Medical School in Worcester.
MSUD is caused by mutated copies of metabolic genes that prevent the body from breaking down certain amino acids. The condition gets its name from a telltale sweet scent that wafts from the urine, sweat and earwax of children with the disease. Though it has a whimsical name, the condition is serious—the toxic buildup of the amino acids can lead to a swollen pancreas, osteoporosis and brain damage, among other symptoms.
The disease requires patients to manage their symptoms with a specialized diet that limits certain meats, legumes and dairy products. There is no cure beyond a liver transplant for certain forms of MSUD.
Two of the most common forms of the disease, MSUD types 1A and 1B, are caused by dysfunctional copies of the BCKDHA and BCKDHB genes, respectively, which code for a metabolic enzyme called branched-chain α-ketoacid dehydrogenase (BCKDH). In the study, researchers used an adeno-associated virus vector to deliver functional copies of the genes to the skeletal muscle, livers, hearts and brains of the study animals.
One of the new study’s authors, Donald Hardin, is a cattle raiser in Indiana who noticed multiple calves across three generations were born with a disease that caused them to quickly deteriorate and die. Hardin reached out to another one of the study’s authors to investigate, which led the team to identify the disease as MSUD. Several of Hardin’s cattle carry mutated copies of the BCKDHA gene.
The scientists bred carriers of the gene to produce a calf with MSUD, and, after saving it from the same fate as the earlier calves, they gave it a one-time injection of the gene therapy. Since being given the therapy, the calf has survived for more than two years and grown to a normal weight, the scientists reported, with no behavioral or neurological symptoms.