Federal Project Grant Award Summary

Brigham and Women's Hospital Inc. received a $479,687 Project Grant award from the National Institute of Neurological Disorders and Stroke (NINDS) under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853), effective March 6, 2026, with an ultimate completion date of February 29, 2028. The award supports research to identify and restore mechanisms driving epilepsy associated with Dentatorubral-Pallidoluysian Atrophy (DRPLA), a rare inherited neurodegenerative disease caused by CAG repeat expansions in the Atrophin-1 (ATN1) gene. The research employs both preclinical humanized in vitro and in vivo model systems, including patient-specific induced pluripotent stem cell (iPSC)-derived cortical neurons and novel transgenic mouse models, to elucidate the molecular and cellular mechanisms underlying neuronal hyperexcitability and drug-resistant seizures in DRPLA patients.

The project delivers research products and findings focused on understanding how ATN1 mutations lead to altered neuronal network activity, including increased calcium spike amplitude and hypersynchronization characteristic of epileptiform phenotypes. The research platform is designed to facilitate translational assessment of innovative therapeutic approaches for symptomatic seizure control and disease modification. Preliminary findings indicate that neuronal hyperexcitability observed in vitro and altered seizure thresholds demonstrated in vivo can be rescued through exogenous therapeutic administration, providing a foundation for potential clinical translation and treatment development for this severe pediatric neurological disorder.