Antisense for the Most Common ALS Gene Appears Safe in Initial Study

November 1, 2013

In work supported by The ALS Association and published in the Proceedings of the American Academy of Science, researchers showed that reducing the production of an ALS-causing gene mutation in mice is safe over the long term. This provides support for moving this therapy forward in people with ALS, whose disease is caused by mutations in this gene, called C9orf72.

“These results are very encouraging for the field, as we develop new approaches to ALS therapy based on specific gene defects,” said Lucie Bruijn, Ph.D., Chief Scientist for The Association. “Targeting this mutation has the potential to be a significant form of therapy for many ALS patients.”

The C9orf72 gene is the most common genetic cause of ALS, accounting for more than a quarter of all familial cases and more than 5 percent of sporadic cases. The mutation is a large expansion of a six-nucleotide repeat unit, GGGGCC. The normal gene contains no more than 30 of these units, while the mutant gene may contain many dozens to hundreds of them. The mutant gene produces a long and sticky strand of RNA, which clumps together and interferes with cell function through unknown means.

In the study, researchers showed that targeting the RNA with so-called antisense oligonucleotides (ASOs) over several months effectively reduced the amount of mutant RNA and produced no worrisome effects in the mice, either at the tissue level or on behavior. “Our findings support that ASO therapy to reduce hexanucleotide repeat-containing RNAs is a rational, promising approach” for treatment of ALS, the authors concluded.

The study was funded by The Association’s Greater Philadelphia Chapter and conducted by Clotilde Lagier-Tourenne, Ph.D., and led by John Ravits, M.D., Ph.D., and Don Cleveland, Ph.D., all of the University of California at San Diego. Two co-authors, Shuying Sun, Ph.D., and Qiang Zhu, Ph.D., also of UCSD, are recipients of The Milton Safenowitz Post-Doctoral Fellowship for ALS Research Award. This award encourages and facilitates promising young scientists to enter the ALS field. Funding for this two-year research award is made possible by the generosity of the Safenowitz family through the Greater New York Chapter of The ALS Association and is in memory of Mr. Safenowitz, who died of ALS in 1998. Dr. Lagier-Tourenne is a previous recipient of the same award.

Read the press release.

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