Gene Therapy for Maple Syrup Urine Disease

Researchers at UMass Chan Medical School have developed a gene therapy for maple syrup urine disease (MSUD) that successfully prevented newborn death, normalized growth, and stabilized biomarkers in both mice and a calf, offering hope for a breakthrough treatment.

A Potential Cure for Maple Syrup Urine Disease

A new study published in Science Translational Medicine demonstrates the potential of gene therapy to treat maple syrup urine disease (MSUD), a rare genetic metabolic disorder. The treatment, developed at UMass Chan Medical School, successfully corrected the genetic mutation responsible for the disease in both mouse models and a calf, paving the way for human clinical trials.

MSUD is caused by mutations in the BCKDHA, BCKDHB, or DBT genes, preventing the body from breaking down certain amino acids. This leads to a buildup of toxic substances, resulting in neurological crises, brain injury, and organ damage. Current treatment options are limited to a strict diet or liver transplantation, making the development of gene therapy a significant advancement.

Study Findings: Gene Therapy Restores Normal Function

The research team designed a recombinant adeno-associated virus serotype 9 (AAV9) vector to deliver gene replacements to the liver, muscle, heart, and brain. This single-dose therapy:

• Prevented newborn death in animal models
• Restored normal gene expression in affected organs
• Stabilized metabolic biomarkers
• Demonstrated long-term durability through extended growth phases

According to Dr. Dan Wang, co-principal investigator, the results in the calf model closely resemble the human disease, providing critical insights into pharmacokinetics and long-term effects.

“We believe this therapy holds great promise for patients with MSUD, particularly for those with the most common forms—types 1A and 1B.”

Next Steps: Towards Human Trials

MSUD is extremely rare, occurring in 1 in 197,714 live births, but is more prevalent in certain ethnic groups such as Mennonites, Ashkenazi Jews, and specific populations in Brazil, Portugal, Turkey, and the Philippines. The success of this study brings hope for future human clinical trials, which the researchers are now working to initiate with the U.S. Food and Drug Administration (FDA).

Dr. Kevin Strauss, a key collaborator, emphasized the groundbreaking potential of this work:

“For people worldwide living with MSUD, this signifies major progress on the path to a brighter future.”

If successful in clinical trials, this gene therapy could replace lifelong dietary restrictions and invasive liver transplants, significantly improving quality of life for MSUD patients.

More Information: Jiaming Wang et al, BCKDHA-BCKDHB digenic gene therapy restores metabolic homeostasis in two mouse models and a calf with classic maple syrup urine disease, Science Translational Medicine (2025). DOI: 10.1126/scitranslmed.ads0539