Biomarker development for C9orf72 repeat expansion in ALS

• Biomarkers are critical for effective clinical trial development in ALS.
• Repeat expansion in C9orf72 represents the most common genetic mutation in ALS to date.
• Mutant C9orf72 pathogenesis offers several biomarker readouts.
• Brain imaging techniques may offer possibilities to biomark C9orf72.
• Molecular and protein biomarkers are detectable in cerebral spinal fluid or blood.

The expanded GGGGCC hexanucleotide repeat in the non-coding region of the C9orf72 gene on chromosome 9p21 has been discovered as the cause of approximately 20–50% of familial and up to 5–20% of sporadic amyotrophic lateral sclerosis (ALS) cases, making this the most common known genetic mutation of ALS to date. At the same time, it represents the most common genetic mutation in frontotemporal dementia (FTD; 10–30%). Because of the high prevalence of mutant C9orf72, pre-clinical efforts in identifying therapeutic targets and developing novel therapeutics for this mutation are highly pursued in the hope of providing a desperately needed disease-modifying treatment for ALS patients, as well as other patient populations affected by the C9orf72 mutation. The current lack of effective treatments for ALS is partially due to the lack of appropriate biomarkers that aide in assessing drug efficacy during clinical trials independent of clinical outcome measures, such as increased survival. In this review we will summarize the opportunities for biomarker development specifically targeted to the newly discovered C9orf72 repeat expansion. While drugs are being developed for this mutation, it will be crucial to provide a reliable biomarker to accompany the clinical development of these novel therapeutic interventions to maximize the chances of a successful clinical trial.This article is part of a Special Issue entitled ALS complex pathogenesis.