Tackling Maple Syrup Urine Disease (MSUD) with Engineered Microbes

Maple syrup urine disease (MSUD) is a rare genetic disorder due to mutations in the mitochondrial multi-enzyme complex called branched-chain α-ketoacid dehydrogenase (BCKDH) which is required to break down the three branched-chain amino acids (BCAAs), i.e., leucine (Leu), isoleucine and valine in the body. MSUD results in the abnormal accumulation of all three BCAAs, along with their various byproducts, throughout the body causing poor feeding, vomiting, dehydration, lethargy, hypotonia, seizures, hypoglycemia, ketoacidosis, pancreatitis, coma and neurological decline. The estimated prevalence is around 1/150,000 live births. Currently, the available treatments are dietary restriction and liver transplantation; no approved therapy exists, resulting in a significant unmet medical need. Synlogic is using its proprietary engineering technology to produce modified probiotic bacteria (Synthetic Bioticsä) capable of rapidly degrading BCAAs originating from food intake, thereby preventing their toxic accumulation. Our studies show that 1) engineered strains can consume sufficient Leu in vitro to address the substrate burden in MSUD patients; 2) MSUD mice administered engineered bacteria show statistically significant lowering of plasma Leu levels compared to controls; 3) behavioral differences are noted between treated mice and controls, consistent with a relief of the toxic effects of excess Leu accumulation; and 4) a trend towards lower Leu levels was observed in brains of treated mice. These data support the concept of an orally-administered engineered probiotic as plausible approach to the treatment of MSUD.