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),
element binding protein A (PURA)
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
Pharmaceuticals Inc. was involved with each manuscript and
has antisense oligonucleotide candidates in preclinical development to treat
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