Project Title: Preclinical proof-of-concept of a stage 3 drug to attenuate hyperexcitability-mediated pathophysiologies linked to Frontotemporal Dementia

Grant Name: 2024 CLEAR Operating Grant

Grant Duration: 2024-2026 (two years)

Research Lay Summary:

Frontotemporal Dementia (FTD) is a prevalent fatal neurodegenerative disease linked to the early appearance of aberrant behavioral changes and dementia. A specific type of mutation in the C9orf72 gene underlies most Frontotemporal Dementia cases, although the precise mechanisms by which this mutation leads to disease pathology remain unclear.

Notably, studies from animal models and patient-derived cells suggest that early in disease development, the C9orf72 mutation results in the disruption of neuronal communication, contributing to the onset of neurodegeneration. Dr. Snutch previously developed a drug, Z944, designed to treat neurological disorders characterized by hyperexcitability, a feature also observed in FTD models. Here, they will employ C9orf72 models and test whether Z944 protects against the aberrant hyperexcitability we hypothesize presents at FTD presymptomatic stages and drives disease progression.

Given that there are no current treatments for FTD, they hope to leverage the proof-of-concept studies, together with the late stage of Z944 clinical development, to deliver a promising near term (2-3 years) therapeutic option for FTD patients.