A new cellular model of C9orf72 ALS may facilitate the discovery of therapies for the most common form of the disease. The NSC34-based motor neuron model, which harbors 102 copies of the G4C2 repeat, is stable, isogenic and tetracycline-inducible. The cells, upon induction, exhibited key aspects of C9orf72 ALS including RNA foci and dipeptide repeat proteins, and resulted in reduced viability. No TDP-43 pathology, however, could be detected. The inducible cellular model may help researchers identify small molecule drugs that reduce potentially toxic RNAs and/or dipeptide repeat proteins in C9orf72ALS through the performance of high-throughput screens. The study is published online on February 1 in Human Molecular Genetics.
The strategy complements an existing approach, pioneered by Scripps Institute’s Matthew Disney in Florida, to design and synthesize small molecules that specifically target the tertiary structure of these expanded repeat RNAs, including quadruplexes (see March 2014 and October 2016 news). Reporting in 2014, the scientists, in collaboration with a multi-institutional ALS research team, found that one of these small molecules significantly reduced the number of C9orf72 RNA foci and dipeptide repeat protein inclusions in directly reprogrammed ALS patient-derived neurons (see August 2014 news; Su et al., 2014). The approach, being developed in collaboration with Mayo Clinic’s Leonard Petrucelli in Florida and Johns Hopkins University School of Medicine’s Jeff Rothstein in Maryland, is being optimized and is at the preclinical stage.
Meanwhile, antisense oligonucleotide strategies aiming to reduce levels of C9orf72 repeat RNAs are continuing to push toward the clinic (see May 2016 news). The project, led in part by University of California’s Don Cleveland in San Diego and Jeff Rothstein, is in collaboration with Biogen in Cambridge, Massachusetts and Ionis Pharmaceuticals in California. Stay tuned.
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