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Antisense oligonucleotide (ASO) therapies for ALS are still being tested, but early results hold promise. In fact, animal studies suggest the potential to reverse the progress of ALS.

The first therapeutic use of antisense oligonucleotide (ASO) technology was recorded in the 1970s, and since then, the field has advanced rapidly.1,2

Clinical trials of ASO-based therapies to treat ALS and other neurodegenerative diseases are underway. So far, the FDA has approved two ASO-mediated therapies for neurodegenerative disorders: one for Duchenne muscular dystrophy and another for spinal muscular atrophy.3

“With the rapid development of improved next-generation ASOs toward clinical application, this technology now holds the potential to have a dramatic effect on the treatment of many neurological conditions in the near future,” the researchers wrote in Nature Reviews Neurology in 2018.4

ASO Therapeutics 101

ASOs influence protein production. We know DNA encodes RNA, which is then translated into proteins. In recent years researchers have been looking at the use of compounds that are able to bind messenger RNAs (mRNAs) to inhibit protein expression.5

That’s where antisense oligonucleotides come into play. ASOs are short, single-stranded molecules of DNA. Easily absorbed by cells, they attach themselves to messenger RNA (mRNA) strands

ASOs have the potential to reduce, restore or modify RNA and protein expression. In other words, they can then disrupt the cell’s natural production of a particular protein.6,7 That’s the key: An mRNA’s code is specific to each protein. Scientists can design ASOs specifically to target the production of protein from just one gene — or just one mutation of that one gene.8

This form of gene therapy holds tremendous potential for the treatment of ALS and other neurodegenerative and CNS diseases.

Impact on TDP-43

A buildup of the transactive response DNA-binding protein-43 (TDP-43) occurs in about 97% of people with ALS.9 In animal studies, ASO therapy appeared to reduce the formation of these toxic TDP-43 clumps (aka, aggregates). These findings provide insights into the mechanisms behind the formation of other toxic aggregates in neurodegenerative diseases.10






1 Bennett, C. F.: Therapeutic Antisense Oligonucleotides Are Coming of Age. Annual Review of Medicine 70 (2019)

2 Kwon, D.: Genetic therapies offer new hope against incurable brain diseases. Nature 592, April 2021

3 Leavitt, B. R. and Tabrizi, S. J.: Antisense oligonucleotides for neurodegeneration. Science 367 (2020)

4 Rinaldi, C., Wood, M. Antisense oligonucleotides: the next frontier for treatment of neurological disorders. Nat Rev Neurol 14, 9–21 (2018).

5 Di Fusco, D. et al.: Antisense Oligonucleotide: Basic Concepts and Therapeutic Application in Inflammatory Bowel Disease. Frontiers in Pharmacology 0 (2019)


7 Rinaldi, C., Nat Rev Neurol op. cit.

8 Lewis, P.: Antisense therapy: a promising new way to treat neurological disease. The Conversation 2017

9 Bahia VS, Takada LT, Deramecourt V. Neuropathology of frontotemporal lobar degeneration: a review. Dement Neuropsychol. 2013;7(1):19-26. doi:10.1590/S1980-57642013DN70100004

10 Cook, Casey N et al. “C9orf72 poly(GR) aggregation induces TDP-43 proteinopathy.” Science Translational Medicine vol. 12,559 (2020): eabb3774. doi:10.1126/scitranslmed.abb3774

11 C9orf72 gene MedLinePlus

12 Vildan, C. et al.: Genetic alterations of C9orf72, SOD1, TARDBP, FUS, and UBQLN2 genes in patients with Amyotrophic Lateral Sclerosis. Cogent Medicine 6 (2019)

13 Recent Analysis on Amyotrophic Lateral Sclerosis Clinical Trials, DelveInsight, 2021

14 Miller, T. et al.: Phase 1–2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. The New England Journal of Medicine 383 (2020)

15 McCampbell A, Cole T, Wegener AJ, et al. Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models. J Clin Invest. 2018;128(8):3558-3567. doi:10.1172/JCI99081

16 McCampbell A, J Clin Invest. 2018 op cit


18 “Antisense Oligonucleotides: Can They Take on ALS, SMA, Prions?” | ALZFORUM May 22, 2019



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