A New Model of C9orf72 ALS Cycles In

A new strategy enters the C9orf72 drug discovery ring. The approach, which is based on a new, inducible motor neuronal cell model, aims to give C9orf72 ALS a one-two punch by reducing synthesis of dipeptide repeat proteins and levels of repeat-containing RNAs. [Gitler and Tsuiji, 2016 under CC-BY-NC-ND 4.0 license.]

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.


Stopford MJ, Higginbottom A, Hautbergue GM, Cooper-Knock J, Mulcahy PJ, De Vos KJ, Renton AE, Pliner H, Calvo A, Chio A, Traynor BJ, Azzouz M, Heath PR, Consortium I, Consortium N, Kirby J, Shaw PJ. C9ORF72 hexanucleotide repeat exerts toxicity in a stable, inducible motor neuronal cell model, which is rescued by partial depletion of Pten. Hum Mol Genet. 2017 Feb 1. doi: 10.1093/hmg/ddx022. [PubMed].

Su Z, Zhang Y, Gendron TF, Bauer PO, Chew J, Yang WY, Fostvedt E, Jansen-West K, Belzil VV, Desaro P, Johnston A, Overstreet K, Oh SY, Todd PK, Berry JD, Cudkowicz ME, Boeve BF, Dickson D, Floeter MK, Traynor BJ, Morelli C, Ratti A, Silani V, Rademakers R, Brown RH, Rothstein JD, Boylan KB, Petrucelli L, Disney MD. Discovery of a biomarker and lead small molecules to target r(GGGGCC)-associated defects in c9FTD/ALS. Neuron. 2014 Sep 3;83(5):1043-50. [PubMed].

Further Reading:

Gitler AD, Tsuiji H. There has been an awakening: Emerging mechanisms of C9orf72 mutations in FTD/ALS. Brain Res. 2016 Sep 15;1647:19-29. [PubMed].

Haeusler AR, Donnelly CJ, Rothstein JD. The expanding biology of the C9orf72 nucleotide repeat expansion in neurodegenerative disease. Nat Rev Neurosci. 2016 Jun;17(6):383-95.[PubMed]. 

c9orf72 disease-als topic-preclinical topic-researchmodels
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