Project Grant R01HD122293

The National Institute of Child Health and Human Development awarded Icahn School of Medicine at Mount Sinai $726,448 on August 13, 2026, under the Child Health and Human Development Extramural Research program (CFDA 93.865) to discover novel inhibitors of the AASS enzyme as a treatment for glutaric aciduria type 1 through substrate reduction.

Glutaric aciduria type 1 (GA1) is an autosomal recessive inborn error of metabolism caused by deficiency of glutaryl-CoA dehydrogenase, leading to accumulation of neurotoxic glutaric acid and 3-hydroxyglutaric acid. Current treatment relies on strict dietary management and emergency intervention to limit metabolite accumulation, but neurological disease still develops in approximately 25 percent of patients despite meticulous adherence. The investigators propose to inhibit 2-aminoadipic semialdehyde synthase (AASS), the enzyme initiating lysine degradation, using allosteric inhibitors targeting the lysine-2-oxoglutarate reductase domain. This upstream intervention is hypothesized to divert neurotoxic metabolite accumulation into more tolerable compounds. The research capitalizes on the observation that genetic AASS deficiency causes hyperlysinemia, considered a benign biochemical phenotype, and leverages previously identified brain-penetrant LOR inhibitors from high-throughput screening to optimize treatment candidates.

Work is performed in New York, New York, with performance through July 31, 2031. The award is a Project Grant, the standard assistance type for NIH research.