Frontotemporal Dementia (FTD) is a brain disorder affecting the frontal and temporal lobes, leading to changes in behavior, personality, speech, and movement. Generally appearing between ages 40 and 65, it impacts roughly 1 in 5,000 people and is devastating to individuals and families. About 40% of FTD cases are familial, with 15-20% genetically linked to mutations in genes like MAPT, GRN, and C9orf72. The other 60% are sporadic, without a clear genetic link, although genetics might still contribute. Amyotrophic Lateral Sclerosis (ALS) is a brain disorder characterized by motor neuron loss, causing muscle weakness, paralysis, and respiratory failure. ALS and FTD share genetic causes, especially C9orf72, the most dominant genetic factor in both. There are currently no effective treatments for either disorder.

The goal of this proposal is to advance a novel, potent, selective and highly brain-penetrant Colony Stimulating Factor 1 Receptor (CSF1R) inhibitor toward clinical trials for FTD and ALS, and identify optimal therapeutic biomarkers. CSF1R is crucial for modulating the brain’s immune response, and is predominantly expressed on microglia cells in the brain. We have generated compelling cellular and animal data that shows CSF1R inhibition can reprogram microglia into a neuroprotective state in genetic forms of FTD and ALS, and potentially slow or halt disease progression.

This proposal significantly progresses our novel CSF1R inhibitor towards human clinical trials where we will assess therapeutic benefit across FTD and ALS genetic and sporadic subtypes. If successful, this compound could be a new treatment for FTD and ALS, with encouraging applicability in the literature to other neurodegenerative diseases like Alzheimer's Disease.