Abstract
A hexanucleotide repeat expansion in the C9orf72 gene is a common genetic cause of ALS and FTD. The repeats are translated into five different dipeptide repeat proteins (DPRs). In this issue, Lehmer et al (2017) demonstrate that one of these DPRs, poly(GP), can be measured in the CSF of individuals with C9orf72 mutations. In conjunction with the findings from another recent study (Gendron et al, 2017), these DPR biomarkers may prove to be extremely valuable in the quest for effective therapies for C9FTD/ALS.
Highlights
A hexanucleotide repeat expansion in the C9orf72 gene is a common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)
There is great excitement at the prospect of imminent clinical trials, it is critical we apply the lessons from past failures
In ALS, despite numerous Phase II/III clinical trials of potential therapeutics, only one drug, riluzole, has been shown to have a minimal effect on prolonging survival. The reasons for this are multifactorial (Mitsumoto et al, 2014), but one key factor that will facilitate better studies is demonstrating that biological effects are dependent on target engagement in appropriate and robust preclinical models and in subsequent clinical trials
Summary
A hexanucleotide repeat expansion in the C9orf72 gene is a common genetic cause of ALS and FTD. Building upon a previous study in a smaller cohort (Su et al, 2014), they validate that CSF poly(GP) is a sensitive and specific biomarker of C9orf72 expansions using Meso Scale Discovery immunoassays, in both asymptomatic and symptomatic individuals.
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