The newly discovered expanded GGGGCC hexanucleotide repeat in the non-coding region of the C9ORF72 gene on chromosome 9 represents the most common genetic abnormality in familial frontotemporal dementia (FTD; 10-30%), familial amyotrophic lateral sclerosis (ALS)/FTD (up to 80%), familial ALS (20-50%) and non-familial (sporadic) ALS (5-20%). Recent studies suggest that the mutation causes brain damage thru RNA toxicity. We have recently developed candidate therapies for this common mutation, thru the use of antisense oligonucleotides, in collaboration with ISIS Pharmaceuticals. This novel approach to inactivating human genes is already in study in other adult and childhood neurological disease and represents a great step forward in personalized brain therapies. In order to be successful as therapy- appropriate markers for drug efficacy will be necessary before any clinical trial will commence. This proposal will build on our prior work on antisense therapy for this gene defect- by developing drug efficacy biomarkers to be used in conjunction with future clinical trials. Together the antisense agents and the appropriate biomarkers of drug action will provide the most compelling science to move this therapy into the clinic in the near term.