Scientists have been chasing C9ORF72 with antisense oligonucleotides ever since the gene and its transcript were linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. On October 16, one research group claimed some success (see related news story). Now, hot on their heels comes a second report. In the October 23 Science Translational Medicine, Robert Baloh and colleagues at Cedars-Sinai Medical Center in Los Angeles describe similar results—antisense RNA rescues C9ORF72 toxicity in cell lines. Together, the two papers strengthen the case that C9ORF72 mRNA aggregates, which accumulate in neurons of people with an expanded version of the gene, contribute to ALS and FTD pathology.

“Now two different labs, using induced pluripotent stem cells, have validated a couple things,” commented Jeffrey Rothstein of Johns Hopkins University in Baltimore, the senior author on the first paper. First, both showed that patient-derived cell lines developed toxic C9ORF72 RNA aggregates, akin to those in the brain of people who have the gene expansion. Second, both succeeded in eliminating those aggregates with antisense therapy.

At Cedars-Sinai, first author Dhruv Sareen and colleagues collected skin fibroblasts from four people with ALS who carry the C9ORF72 mutation. Sareen and colleagues converted these cells into iPS cells, and then coaxed those to become motor neurons. The researchers found that the C9ORF72 mutation, a hexanucleotide expansion, altered the expression of several genes in the cells, something Rothstein’s group also observed. Sareen and colleagues also found that compared with control neurons, the patient-derived cells fired nerve impulses poorly. In both studies, the C9ORF72 cells filled with punctate aggregates containing C9ORF72 expanded RNA and RNA-binding proteins. “There is clearly some abnormality in the cells,” Baloh said.

In addition to the RNA foci, Rothstein and colleagues detected aggregates of peptides created by abnormal translation of the expanded C9ORF72 mRNA. However, Baloh's group found none of these aggregates. Baloh speculated that might be because his group made motor neurons and not generic neurons. Rothstein's and another group observed these peptide aggregates in generic neurons derived from iPS cells (see Almeida et al., 2013). In another recent paper, researchers reported that the aggregates crop up in the brain but not motor neurons ( Mackenzie et al., 2013). The researchers who originally identified these mistranslated peptides found them in human brain tissue, but did not examine spinal motor neurons (see related news story, related news story).

Both groups treated the cultures with antisense oligonucleotides from Isis Pharmaceuticals of Carlsbad, California. Each found that antisense treatment reversed the gene expression changes caused by the C9ORF72 expansion and dissolved the RNA aggregates. Isis makes a cholesterol-lowering drug that is the only antisense treatment ever approved by the FDA for systemic treatment, and its antisense treatment for mutant superoxide dismutase appeared safe in phase 1 trials for ALS (see related news story on Miller et al., 2013).

While the new data hints that antisense might work in people with C9ORF72 expansions, there are a few hurdles to leap before initiating a clinical trial, researchers agreed. Baloh suggested that animal experiments would shore up the case for human studies. While it may prove difficult to create a mouse that mimics C9ORF72 pathology, he would like to see antisense treatment knock down C9ORF72 in an animal expressing the human gene.—Amber Dance


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News Citations

  1. RNA Deposits Confer Toxicity in C9ORF72 ALS
  2. RNA Twist: C9ORF72 Intron Expansion Makes Aggregating Protein
  3. Second Study Sees Intron in FTLD Gene Translated
  4. Paper Alert: Antisense Oligonucleotide Therapy Safe for ALS?

Paper Citations

  1. . Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons. Acta Neuropathol. 2013 Sep;126(3):385-99. PubMed.
  2. . Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinico-pathological correlations. Acta Neuropathol. 2013 Dec;126(6):859-79. Epub 2013 Oct 6 PubMed.
  3. . An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol. 2013 May;12(5):435-42. Epub 2013 Mar 29 PubMed.

Further Reading


  1. . Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALS. Acta Neuropathol. 2013 Oct 16; PubMed.
  2. . Loss of function of C9orf72 causes motor deficits in a zebrafish model of Amyotrophic Lateral Sclerosis. Ann Neurol. 2013 May 30; PubMed.

Primary Papers

  1. . Targeting RNA Foci in iPSC-Derived Motor Neurons from ALS Patients with a C9ORF72 Repeat Expansion. Sci Transl Med. 2013 Oct 23;5(208):208ra149. PubMed.