A C9ORF72 Pipeline for ALS Drug Discovery and Treatment
Abstract
A breakthrough in amyotrophic lateral sclerosis (ALS) research came in 2011 when a GGGGCC repeat expansion was identified in the first intron of chromosome 9 open reading frame 72 (C9ORF72), an evolutionarily conserved gene of unknown function, in both familial and sporadic ALS and frontotemporal dementia cases. Of clinical significance is the high incidence of ALS cases associated with this mutation: around 40% of familial and 7% of sporadic ALS cases occur in individuals with European ancestry. Although some progress has been made in generating C9ORF72 animal models, many do not show disease phenotypes, leaving an urgent need for new models for therapeutic discovery. The only approved drug to slow the progression of ALS, riluzole, is modestly effective. Our group has previously worked together as a part of drug screening platform to identify neuroprotective molecules using in vivo models of TDP-43 toxicity. This work culminated in the discovery of pimozide in a collaborative Phase II human clinical trial at the University of Calgary (CLINICALTRIALS.GOV NCT02463825). We propose to establish a new pipeline for ALS drug development focusing on C9ORF72 s role in ALS pathogenesis. Our multidisciplinary approach uses several C9ORF72 in vivo models for drug discovery and validation to identify compounds suitable for clinical testing. The pathogenic mechanisms underlying C9ORF72 repeat expansion and motor neuron degeneration are unknown, but may involve both loss-of-function and gain-of-function mechanisms. We have conducted an unbiased screen of nearly 4,000 compounds (many Food and Drug Administration approved) in a C. elegans C9ORF72 loss-of-function model and identified several neuroprotective molecules. We have developed transient, plasmid expression vectors that express GGGGCC repeats in either C. elegans or zebrafish, which in turn results in neural degeneration phenotypes confirming the usefulness of these simple models. We are in the process of counter-screening the hits from the loss-of-function screen in the C. elegans and zebrafish models. To advance our platform approach, we will develop and screen genetically appropriate C. elegans and zebrafish GGGGCC knock-in models as part of a multisystem C9ORF72 drug-screening endeavor. Finally, we will generate iPS-derived motor neuron cell lines from ALS patients with C9ORF72 mutations to test and validate the compounds identified from our screens. Our collaborative, multi-model system, drug discovery approach will identify small molecules that reduce toxicity associated with C9ORF72 mutations. In this 24-month proposal, we expect to identify two to three lead compounds that could be further evaluated in rodent models as well as clinical settings.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710080
Entities
People
- Alex Parker
Organizations
- Centre hospitalier de l'Université de Montréal
- United States Army