Maple syrup urine disease (MSUD) is a rare genetic inborn error of metabolism characterized by recurrent life-threatening neurologic crises and progressive brain injury. The disease is typically caused by biallelic mutations in genes (branched-chain α-ketoacid dehydrogenase E1α (BCKDHA), E1β (BCKDHB), or dihydrolipoamide branched-chain transacylase (DBT)) subunits which interact to form the mitochondrial BCKDH complex that decarboxylates ketoacid derivatives of leucine, isoleucine, and valine. MSUD can be treated by a strictly controlled diet or allogeneic liver transplantation.
Now, new work demonstrates that a gene therapy prevented newborn death, normalized growth, restored coordinated expression of the affected genes, and stabilized biomarkers in a calf as well as in mice.
This work is published in Science Translational Medicine in the paper, “BCKDHA-BCKDHB digenic gene therapy restores metabolic homeostasis in two mouse models and a calf with classic maple syrup urine disease.”
“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,” said Dan Wang, PhD, assistant professor of genetic & cellular medicine at UMass Chan Medical School.
More specifically, in two models of severe MSUD (Bckdha−/− and Bckdhb−/− mice) and a newborn calf homozygous for BCKDHA c.248C>T, “one postnatal injection prevented perinatal death, normalized growth, restored coordinated expression of BCKDHA and BCKDHB in the skeletal muscle, liver, heart, and brain, and stabilized MSUD biomarkers in the face of high protein ingestion.”
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 Kevin Strauss, MD, adjunct professor of pediatrics and head of therapeutic development at the Clinic for Special Children in Gordonville, PA.
Wang said that researchers are exploring with the FDA the next steps to translate this gene therapy into clinical use as a Phase I/II study. The study 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.