Gene therapy for maple syrup urine disease shows promise

Scientists have created a new gene therapy for a debilitating genetic disorder called maple syrup urine disease (MSUD). The treatment can prevent recurrence of deadly symptoms in a cow calf born with the disease. Their protocol could one day be translated into a much-needed therapy for patients with two types of classic MSUD, who currently face limited treatment options. Results were published in Science Translational Medicine.

Classic MSUD arises from mutations in the three genes that encode the protein subunits of the branched chain alpha-keto acid dehydrogenase complex (BCKDH). The loss of this complex prevents the body from properly breaking down several amino acids, eventually leading to neurological symptoms and life-threatening brain damage. To prevent complications, patients must either follow a very strict diet low in protein or receive a liver transplant.

Now, Dr. Jiaming Wang from the University of Massachusetts Chan Medical School, Worcester, Massachusetts and others present a new gene replacement therapy for two types of classic MSUD that uses an adeno-associated viral vector to deliver functional gene copies of BCKDHA and BCKDHB systemically. The therapy worked as intended in knockout cells and was safe in wild-type mice, and also prevented death after birth in mice deficient in either BCKDHA or BCKDHB.

The scientists visited a farm where some newborn calves had perished from classic MSUD. They worked with the farmer to breed a calf with MSUD and administered a single dose of their gene therapy, modified to carry bovine genes, to the animal. Over the next two years, the calf grew normally and was eventually able to transition to a normal bovine diet high in protein.

The team plans on further work to characterize the long-term impact of the gene therapy on BCKDH levels in the brain, as well as to determine the treatment’s benefits on cognition and behaviour over longer study periods.