Understanding the pathophysiology and development of new therapeutics for dementias such as Alzheimer's and frontotemporal dementia (FTD) has been an enormous challenge. In this application we propose to study molecular events that may contribute to the disease of a newly discovered common gene mutation C9ORF72 which is commonly found in both FTD (11.7%) as well as amyotrophic lateral sclerosis (ALS, 30-50%). We will employ FTD/ALS patient-derived human fibroblasts and convert them into adult induced pluripotent stem (iPS) cells as well as differentiated relevant central nervous system (CNS) cell types such as astroglia and motor neurons. The ability to actually have human cell lines that represent the natural disease by carrying hereditary gene mutations will provide unprecedented tools. These human cells will undergo a thorough analysis of their molecular genetic composition, which will then be compared to the genetic profile of human cells obtained from normal, healthy volunteers. Based on the differences we will design and develop a molecular therapeutic agent (antisense oligonucleotide) targeted at the specific mutation responsible for the disease. We will further develop a so called biomarker which will allow us to non-invasively monitor the efficacy of these novel drugs when given to patients. The use of these human cells may allow us to efficiently and quickly develop a drug therapy for C9ORF72 form of FTD and/or ALS.