Amyotrophic lateral sclerosis (ALS), or more widely known as “Lou Gehrig's Disease”, is a progressive neurodegenerative disorder that causes muscle weakness, disability, and eventually death. ALS is a disease that can be passed from parent to child, affecting multiple family members across several generations. But the disease can also develop sporadically, affecting families where there is no history of the disease. To date there is no cure for ALS. Medical care is focused primarily on the management of symptoms of disease, which can provide ALS patients with a longer window of independence and prolonged survival.
Although there has been a lot of research into the causes of ALS, no one gene or factor has been identified as the cause of the disease. A host of environmental conditions have been implicated as well as a number of genes. A recently identified six nucleotide (GGGGCC) repeat expansion in the C9ORF72 gene is the most common genetic abnormality identified in both inherited and sporadic ALS. Healthy people will have approximately 30 repeats of this nucleotide sequence, but ALS patients can have 250 to 1,600 repeats. Although the exact mechanism by which the repeat expansion causes ALS is unknown, recent findings from another neurodegenerative disorder, Myotonic Dystrophy, which is caused by a different repeat expansion, suggest these abnormally long expansions produce toxic RNAs that accumulate and lead to cell death. Because Isis’ antisense technology can target specific RNAs for degradation, antisense is uniquely applicable to treat diseases caused by toxic RNAs such as Myotonic Dystrophy and the new ALS gene, C9ORF72. Isis has already demonstrated the feasibly of this approach with ISIS-DMPKRx, an antisense drug designed to selectively target and eliminate the toxic RNA responsible for myotonic dystrophy type 1.
In three ground-breaking studies recently published in Neuron1, Science Translation Medicine (STM)2 and Proceedings of the National Academy of Sciences (PNAS)3, Isis and collaborators evaluated whether antisense compounds designed to target and eliminate the toxic RNA produced by C9ORF72 could inhibit accumulation of toxic RNA in cells derived from ALS patients.
In the studies published in Neuron and STM, researchers applied antisense drugs designed to target the repeat expansions in the C9ORF72 gene to neurons derived from ALS patients. In these studies, antisense compounds significantly decreased toxic RNA and restored normal cell function in ALS neurons. In a separate study, researchers from Dr. Cleveland’s lab, a long-time Isis collaborator, also demonstrated that antisense targeting of the C9ORF72 repeat expansion reduced the accumulation of toxic RNA in the cells, and further demonstrated that toxic RNAs may be generated from both strands of the gene (sense and antisense RNAs).
Together, these results suggest that antisense-mediated reduction of toxic RNA is an effective approach to removing toxic RNA and restoring normal cellular function in cells derived from patients with ALS. These consistent findings, from three separate research groups, provide strong scientific support for advancing an antisense strategy to treat ALS patients.
1Donnelly, C.J. et al. (2013) RNA Toxicity from the ALS/FTD C9ORF72 Expansion Is Mitigated by Antisense Intervention. Neuron. 80:415-28.
2Sareen, D. et al. (2013) Targeting RNA foci in iPSC-derived motor neurons from ALS patients with C9ORF72 repeat expansion. Science Translation Medicine. 5:208ra149.
3Lagier-Tourenne, T. et al. (2013) Targeted degradation of sense and antisense C9orf72 nuclear RNA foci as therapy for amyotrophic lateral sclerosis and frontotemporal demential. PNAS. Published ahead of print October 29, 2013.