PROJECT SUMMARY/ABSTRACT Frontotemporal dementia, often classified as Alzheimer’s disease related dementia, is a devastating disease with a common onset between the ages of 40 to 65 that affects estimated >50,000 people just in the US. The disease is a result of progressive degeneration of frontal and temporal lobes of the brain that can result in wide variety of devastating symptoms including severe behavioral changes, speech and language problems, motor disorders, and survival of 3-12 years, but no therapies slowing the progression of this age-related neurodegenerative disease are available. We propose undertaking a project to rapidly discover a novel oligonucleotide therapeutic for direct modulation of a genetically validated target involved in pathologic neuroinflammation. Microglia-driven neuroinflammation has emerged as a critical pathologic mechanism in FTD and other age-related neurodegenerative diseases. We found that our target expression level is significantly increased in FTD-ALS, which is the most severe version of FTD. Consistently with published literature from other neurodegenerative diseases, we find that the lower expression of the genetic target is correlated with longer patient survival, and its hypomorphic gene variant is associated with late disease onset. This project leverages our high-throughput iPSC platform with diverse genetic models of FTD to provide robust functional evidence for further development of the candidate drug. Successful completion of the proposed drug discovery project will deliver a candidate therapeutic for FTD that will be ready for in vivo studies. The mission of our company is to efficiently deliver novel therapeutics to patients with devastating age-related diseases using our lean company model and high-throughput, automated drug discovery platform anchored in human genomic data paired with clinical measurements.