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Amyotrophic lateral sclerosis (ALS)

Chromosome 9 open reading frame 72 (C9orf72)

Studies in patient samples and mice suggest antisense oligonucleotides targeting the hexanucleotide repeat in C9orf72 could help treat some patients with ALS. GGGGCC repeats in C9orf72 represent the most common genetic cause of ALS. In postmortem brain tissue from patients with ALS or various types of neurons derived from ALS patient fibroblasts carrying the repeats, RNA foci formed and sequestered RNA-binding proteins, including heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1), purine-rich element binding protein A (PURA) and adenosine deaminase RNA-specific B2 (ADARB2). These RNA foci disrupted normal gene splicing and transcription and induced glutamate-mediated excitotoxicity. In the ALS neurons or tissues, antisense oligonucleotides targeting C9orf72 or the repeat expansions suppressed RNA foci formation and partially corrected expression of the dysregulated genes. They also decreased glutamate-induced excitotoxicity compared with scrambled antisense oligonucleotides. In normal mice, C9orf72 antisense oligonucleotides were well tolerated and did not cause any symptoms of ALS. Next steps include selecting the best antisense oligonucleotide for clinical development.
Isis Pharmaceuticals Inc. was involved with each manuscript and has antisense oligonucleotide candidates in preclinical development to treat ALS.

SciBX 6(45); doi:10.1038/scibx.2013.1298
Published online Nov. 21, 2013

For all three studies, patent applications filed by Isis Pharmaceuticals covering antisense oligonucleotides; unavailable for licensing

Sareen, D. et al. Sci. Transl. Med.; published online Oct. 23, 2013;
Contact: Robert H. Baloh,
Cedars-Sinai Medical Center,
Los Angeles, Calif.

Donnelly, C.J. et al. Neuron; published online Oct. 16, 2013;
Contact: Jeffrey D. Rothstein,
The Johns Hopkins University, Baltimore, Md.
Contact: Rita Sattler, same affiliation as above

Lagier-Tourenne, C. et al. Proc. Natl. Acad. Sci. USA; published online Oct. 29, 2013;
Contact: John Ravits, University of California, San Diego, La Jolla, Calif.
Contact: Don W. Cleveland,
same affiliation as above