Application of Antisense Oligonucleotide Drugs in Amyotrophic Lateral Sclerosis and Huntington's Disease

Overview

Journal Transl Neurodegener

Publisher Biomed Central

Date 2025 Jan 22

PMID 39838446

Authors

Kaili Ou

Qingqing Jia

Dandan Li

Shihua Li

Xiao-Jiang Li

Peng Yin

Affiliations

Soon will be listed here.

Abstract

Amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD) are diverse in clinical presentation and are caused by complex and multiple factors, including genetic mutations and environmental factors. Numerous therapeutic approaches have been developed based on the genetic causes and potential mechanisms of ALS and HD. Currently, available treatments for various neurodegenerative diseases can alleviate symptoms but do not provide a definitive cure. Gene therapy, which aims to modify or express specific proteins for neuroprotection or correction, is considered a powerful tool in managing neurodegenerative conditions. To date, antisense oligonucleotide (ASO) drugs targeting the pathological genes associated with ALS and HD have shown promising results in numerous animal studies and several clinical trials. This review provides a comprehensive overview of the development, mechanisms of action, limitations, and clinical applications of ASO drugs in neurodegenerative diseases, with a specific focus on ALS and HD therapeutic strategies.

References

Lim K, Maruyama R, Yokota T . Eteplirsen in the treatment of Duchenne muscular dystrophy. Drug Des Devel Ther. 2017; 11:533-545. PMC: 5338848. DOI: 10.2147/DDDT.S97635. View

Roshmi R, Yokota T . Pharmacological Profile of Viltolarsen for the Treatment of Duchenne Muscular Dystrophy: A Japanese Experience. Clin Pharmacol. 2021; 13:235-242. PMC: 8688746. DOI: 10.2147/CPAA.S288842. View

Shen W, Liang X, Sun H, Crooke S . 2'-Fluoro-modified phosphorothioate oligonucleotide can cause rapid degradation of P54nrb and PSF. Nucleic Acids Res. 2015; 43(9):4569-78. PMC: 4482069. DOI: 10.1093/nar/gkv298. View

Kim Y . Drug Discovery Perspectives of Antisense Oligonucleotides. Biomol Ther (Seoul). 2023; 31(3):241-252. PMC: 10129852. DOI: 10.4062/biomolther.2023.001. View

Gales L . Tegsedi (Inotersen): An Antisense Oligonucleotide Approved for the Treatment of Adult Patients with Hereditary Transthyretin Amyloidosis. Pharmaceuticals (Basel). 2019; 12(2). PMC: 6631675. DOI: 10.3390/ph12020078. View

Mercuri E, Darras B, Chiriboga C, Day J, Campbell C, Connolly A . Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy. N Engl J Med. 2018; 378(7):625-635. DOI: 10.1056/NEJMoa1710504. View

Matsuo M . Antisense Oligonucleotide-Mediated Exon-skipping Therapies: Precision Medicine Spreading from Duchenne Muscular Dystrophy. JMA J. 2021; 4(3):232-240. PMC: 8355726. DOI: 10.31662/jmaj.2021-0019. View

Zhu G, Chen X . Aptamer-based targeted therapy. Adv Drug Deliv Rev. 2018; 134:65-78. PMC: 6239901. DOI: 10.1016/j.addr.2018.08.005. View

Alhamadani F, Zhang K, Parikh R, Wu H, Rasmussen T, Bahal R . Adverse Drug Reactions and Toxicity of the Food and Drug Administration-Approved Antisense Oligonucleotide Drugs. Drug Metab Dispos. 2022; 50(6):879-887. PMC: 11022857. DOI: 10.1124/dmd.121.000418. View

10.

Paganoni S, Macklin E, Hendrix S, Berry J, Elliott M, Maiser S . Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis. N Engl J Med. 2020; 383(10):919-930. PMC: 9134321. DOI: 10.1056/NEJMoa1916945. View

11.

Nomura T, Watanabe S, Kaneko K, Yamanaka K, Nukina N, Furukawa Y . Intranuclear aggregation of mutant FUS/TLS as a molecular pathomechanism of amyotrophic lateral sclerosis. J Biol Chem. 2013; 289(2):1192-202. PMC: 3887186. DOI: 10.1074/jbc.M113.516492. View

12.

Khvorova A, Watts J . The chemical evolution of oligonucleotide therapies of clinical utility. Nat Biotechnol. 2017; 35(3):238-248. PMC: 5517098. DOI: 10.1038/nbt.3765. View

13.

Goutman S, Hardiman O, Al-Chalabi A, Chio A, Savelieff M, Kiernan M . Emerging insights into the complex genetics and pathophysiology of amyotrophic lateral sclerosis. Lancet Neurol. 2022; 21(5):465-479. PMC: 9513754. DOI: 10.1016/S1474-4422(21)00414-2. View

14.

Amado D, Davidson B . Gene therapy for ALS: A review. Mol Ther. 2021; 29(12):3345-3358. PMC: 8636154. DOI: 10.1016/j.ymthe.2021.04.008. View

15.

Kaur S, McKeown S, Rashid S . Mutant SOD1 mediated pathogenesis of Amyotrophic Lateral Sclerosis. Gene. 2015; 577(2):109-18. DOI: 10.1016/j.gene.2015.11.049. View

16.

Benatar M, Wuu J, Andersen P, Bucelli R, Andrews J, Otto M . Design of a Randomized, Placebo-Controlled, Phase 3 Trial of Tofersen Initiated in Clinically Presymptomatic SOD1 Variant Carriers: the ATLAS Study. Neurotherapeutics. 2022; 19(4):1248-1258. PMC: 9587202. DOI: 10.1007/s13311-022-01237-4. View

17.

Ogawa S, Brown H, Okano H, Pfaff D . Cellular uptake of intracerebrally administered oligodeoxynucleotides in mouse brain. Regul Pept. 1995; 59(2):143-9. DOI: 10.1016/0167-0115(95)00096-t. View

18.

Vance C, Rogelj B, Hortobagyi T, De Vos K, Nishimura A, Sreedharan J . Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009; 323(5918):1208-1211. PMC: 4516382. DOI: 10.1126/science.1165942. View

19.

Golsorkhi M, Koch J, Pedouim F, Frei K, Bondariyan N, Dashtipour K . Comparative Analysis of Deutetrabenazine and Valbenazine as VMAT2 Inhibitors for Tardive Dyskinesia: A Systematic Review. Tremor Other Hyperkinet Mov (N Y). 2024; 14:13. PMC: 10941689. DOI: 10.5334/tohm.842. View

20.

Codron P, Cassereau J, Vourch P . InFUSing antisense oligonucleotides for treating ALS. Trends Mol Med. 2022; 28(4):253-254. DOI: 10.1016/j.molmed.2022.02.006. View