Study demonstrates successful gene therapy for maple syrup urine disease

A study led by UMass Chan researchers demonstrated that a gene therapy to correct a mutation that causes maple syrup urine disease (MSUD) prevented newborn death, normalized growth, restored coordinated expression of the affected genes and stabilized biomarkers in a calf as well as in mice. 

Simply put, we believe the gene therapy demonstrated in both animal species, especially in the cow, very well showcases the therapeutic potential for MSUD, in part because the diseased cow, without treatment, has a very similar metabolic profile as the patients."

Dan Wang, PhD, assistant professor of genetic & cellular medicine

Dr. Wang is co-principal investigator with Heather Gray-Edwards, DVM, PhD, assistant professor of genetic & cellular medicine; Guangping Gao, PhD, the Penelope Booth Rockwell Chair in Biomedical Research, director of the Horae Gene Therapy Center, director of the Li Weibo Institute for Rare Diseases Research and chair and professor of genetic & cellular medicine; and Kevin Strauss, MD, adjunct professor of pediatrics and head of therapeutic development at the Clinic for Special Children in Gordonville, Pennsylvania. 

The study, published in Science Translational Medicine, was partially funded through an agreement with ASC Therapeutics, a privately held biopharmaceutical company developing in-vivo gene replacement, gene editing and allogeneic cell therapies. 

MSUD is a rare genetic inborn error of metabolism characterized by recurrent life-threatening neurologic crises and progressive brain injury that can only be managed with an exacting prescription diet or liver transplant from a donor. 

The condition occurs in one in 197,714 live births but is much more common in certain regions of Brazil, Portugal, Turkey, the Philippines, and among people of Ashkenazi or Mennonite descent. Among the Mennonite population such as communities in Lancaster County, Pennsylvania, the incidence of MSUD is one in 400. 

MSUD is caused when a mutated form of the BCKDHA, BCKDHB or DBT gene is inherited from both parents. As a result of this mutation, the body is unable to break down certain parts of proteins. This leads to the build-up of toxic substances that can cause organ and brain damage. 

Researchers in the current study designed a dual-function recombinant adeno-associated virus serotype 9 vector to deliver a gene replacement to the liver, muscle, heart and brain. They wrote that the one-time treatment holds promise as a therapeutic alternative to prescription diet and liver transplant for treatment of MSUD types 1A and 1B, the two most common forms of MSUD in humans. 

Data from the calf translated more directly to humans for purposes of understanding pharmacokinetics, specific treatment effects on muscle and brain tissue, and long-term durability through an extended phase of growth. 

"We believed gene therapy could be a breakthrough for patients with MSUD and, in August 2018, met on a cattle farm in Iowa to pursue that vision: to develop and test gene therapy in a unique animal model, a newborn calf with MSUD," said Dr. Strauss. "In the years that followed, physicians at the Clinic for Special Children worked intently with scientists and veterinarians from UMass Chan Medical School to achieve that goal, drawing their inspiration from the hopes and struggles of the MSUD community. For people worldwide living with MSUD, this signifies major progress on the path to a brighter future." 

Wang said that researchers are exploring with the U.S. Food and Drug Administration the next steps to translate this gene therapy into clinical use as a Phase I/II study.