Treatment implications of C9ORF72

Sharon J Sha, Adam Boxer

Frontotemporal dementia (FTD) is a common dementia syndrome in patients under the age of 65 years with many features overlapping with amyotrophic lateral sclerosis (ALS). The link between FTD and ALS has been strengthened by the discovery that a hexanucleotide repeat expansion in a non-coding region of the C9ORF72 gene causes both familial and sporadic types of these two diseases. As we begin to understand the pathophysiological mechanisms by which this mutation leads to FTD and ALS (c9FTD/ALS), new targets for disease-modifying therapies will likely be unveiled. Putative C9ORF72 expansion pathogenic mechanisms include loss of C9ORF72 protein function, sequestration of nucleic acid binding proteins due to expanded hexanucleotide repeats, or a combination of the two. New animal models and other research tools informed by work in other repeat expansion neurodegenerative diseases such as the spinocerebellar ataxias will help to elucidate the mechanisms of C9ORF72-mediated disease. Similarly, re-examining previous studies of drugs developed to treat ALS in light of this new mutation may identify novel FTD treatments. Ultimately, research consortiums incorporating animal models and well-characterized clinical populations will be necessary to fully understand the natural history of the c9FTD/ALS clinical phenotypes and identify biomarkers and therapeutic agents that can cure the most common form of genetically determined FTD and ALS.