Challenges ahead, but advancements realized
Novel gene-based therapies show significant potential for transforming the treatment of NMDs. The complex pathologies of NMDs have been a huge challenge to disease management in an area once considered unremediable by gene-based therapy. However, advancements in precision medicine – specifically, gene-delivery systems (for example, AAV9 and AAVrh74 vectors) combined with gene modification strategies (ASOs and AAV-mediated silencing) – have the potential to, first, revolutionize standards of care for sporadic and inherited NMDs and, second, significantly reduce disease burden.6
What will be determined to be the “best” therapeutic approach will, likely, vary from NMD to NMD; further investigation is required to determine which agents offer optimal clinical efficacy and safety profiles.43 Furthermore, the key to therapeutic success will continue to be early detection and diagnosis – first, by better understanding disease pathology and drug targets and, second, by validation of reliable biomarkers that are predictive of therapeutic benefit.4,5
To sum up, development challenges remain, but therapeutic approaches to ALS, SMA, and DMD that utilize novel gene-delivery and gene-manipulation tools show great promise.
Ms. Yewhalashet is a student in the masters of business and science program, with a concentration in healthcare economics, at Keck Graduate Institute Henry E. Riggs School of Applied Life Sciences, Claremont, Calif. Dr. Davis is professor of practice in clinical and regulatory affairs, Keck Graduate Institute Henry E. Riggs School of Applied Life Sciences.
References
1. Aitken M et al. Understanding neuromuscular disease care. IQVIA [Internet]. Oct 30, 2018. Accessed Mar 1, 2022. https://www.iqvia.com/insights/the-iqvia-institute/reports/understanding-neuromuscular-disease-care.
2. National Institute of Neurological Disorders and Stroke. Neurological diagnostic tests and procedures fact sheet. Updated Nov 15, 2021. Ac-cessed Mar 1, 2022. http://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Neurological-Diagnostic-Tests-and-Procedures-Fact.
3. Deenen JCW et al. The epidemiology of neuromuscular disorders: A comprehensive overview of the literature. J Neuromuscul Dis. 2015;2(1):73-85.
4. Cavazzoni P. The path forward: Advancing treatments and cures for neurodegenerative diseases. U.S. Food and Drug Administration. Jul 29, 2021. Accessed Mar 1, 2022. http://www.fda.gov/news-events/congressional-testimony/path-forward-advancing-treatments-and-cures-neurodegenerative-diseases-07292021.
5. Martier R, Konstantinova P. Gene therapy for neurodegenerative diseases: Slowing down the ticking clock. Front Neurosci. 2020 Sep 18;14:580179. doi: 10.3389/fnins.2020.580179.
6. Sun J, Roy S. Gene-based therapies for neurodegenerative diseases. Nat Neurosci. 2021 Mar;24(3):297-311. doi:10.1038/s41593-020-00778-1.
7. Amado DA, Davidson BL. Gene therapy for ALS: A review. Mol Ther. 2021 Dec 1;29(12):3345-58. doi:10.1016/j.ymthe.2021.04.008.
8. Yun Y, Ha Y. CRISPR/Cas9-mediated gene correction to understand ALS. Int J Mol Sci. 2020;21(11):3801. doi:10.3390/ijms21113801.
9. National Institute of Neurological Disorders and Stroke. Amyotrophic lateral sclerosis (ALS) fact sheet. Updated Nov 15, 2021. Accessed Mar 1, 2022. http://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Amyotrophic-Lateral-Sclerosis-ALS-Fact-Sheet.
10. Cappella M et al. Gene therapy for ALS – A perspective. Int J Mol Sci. 2019;20(18):4388. doi:10.3390/ijms20184388.
11. Abramzon YA, Fratta P, Traynor BJ, Chia R. The Overlapping Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Front Neurosci. 2020;14. Accessed August 18, 2022. https://www.frontiersin.org/articles/10.3389/fnins.2020.00042
12. Giannini M, Bayona-Feliu A, Sproviero D, Barroso SI, Cereda C, Aguilera A. TDP-43 mutations link Amyotrophic Lateral Sclerosis with R-loop homeostasis and R loop-mediated DNA damage. PLOS Genet. 2020;16(12):e1009260. doi:10.1371/journal.pgen.1009260
13. FDA-approved drugs for treating ALS. The ALS Association [Internet]. Accessed Mar 1, 2022. http://www.als.org/navigating-als/living-with-als/fda-approved-drugs.
14. Jensen TL et al. Current and future prospects for gene therapy for rare genetic diseases affecting the brain and spinal cord. Front Mol Neurosci. 2021 Oct 6;14:695937. doi:10.3389/fnmol.2021.695937.
15. ALS Gene Targeted Therapies. The ALS Association. Accessed August 22, 2022. https://www.als.org/understanding-als/who-gets-als/genetic-testing/als-gene-targeted-therapies
16. Tofersen for ALS clears phase 1/2 trial, now in phase 3. Advances in Motion. Massachusetts General Hospital [Internet]. Sep 30, 2020. Accessed Mar 1, 2022. https://advances.massgeneral.org/neuro/journal.aspx?id=1699.17. Biogen. A study to evaluate the efficacy, safety, tol-erability, pharmacokinetics, and pharmacodynamics of BIIB067 administered to adult subjects with amyotrophic lateral sclerosis and confirmed superoxide dismutase 1 mutation. ClinicalTrials.gov Identifier: NCT02623699. Updated Jul 25, 2021. Accessed Feb 17, 2022. https://clinicaltrials.gov/ct2/show/NCT02623699.
18. Biogen. Biogen announces topline results from the tofersen phase 3 study and its open-label Extension in SOD1-ALS. Press release. Oct 17, 2021. Accessed Mar 1, 2022. https://investors.biogen.com/news-releases/news-release-details/biogen-announces-topline-results-tofersen-phase-3-study-and-its.
19. Biogen. An extension study to assess the long-term safety, tolerability, pharmacokinetics, and effect on disease progression of BIIB067 ad-ministered to previously treated adults with amyotrophic lateral sclerosis caused by superoxide dismutase 1 mutation. ClinicalTrials.gov Identi-fier: NCT03070119. Updated Sep 10, 2021. Accessed Feb 17, 2022. https://clinicaltrials.gov/ct2/show/NCT03070119.
20. MS MW. #AANAM – ATLAS Trial to Assess Tofersen in Presymptomatic SOD1 ALS. Accessed February 19, 2022. https://alsnewstoday.com/news-posts/2021/04/23/aanam-atlas-clinical-trial- tofersen-presymptomatic-sod1-als-patients/
21.Biogen. A phase 3 randomized, placebo-controlled trial with a longitudinal natural history run-in and open-label extension to evaluate BIIB067 initiated in clinically presymptomatic adults with a confirmed superoxide dismutase 1 mutation. ClinicalTrials.gov Identifier: NCT04856982. Updated Feb 18, 2022. Accessed Mar 1, 2022. https://clinicaltrials.gov/ct2/show/NCT04856982.
22. Latozinemab | ALZFORUM. Accessed August 19, 2022. https://www.alzforum.org/therapeutics/latozinemab
23. Alector Presents AL001 (latozinemab) Data from the FTD-C9orf72 Cohort of the INFRONT-2 Phase 2 Clinical Trial | Alector. Accessed August 18, 2022. https://investors.alector.com/news- releas-es/news-release-details/alector-presents-al001-latozinemab-data-ftd-c9orf72-cohort/
24. Alector Announces First Participant Dosed in Phase 2 Study Evaluating AL001 in Amyotrophic Lateral Sclerosis (ALS) | Alector. Accessed August 18, 2022. https://investors.alector.com/news- releases/news-release-details/lector-announces-first-participant-dosed-phase-2-study-0/ 25. A Phase 2 Study to Evaluate AL001 in C9orf72-Associated ALS - Full Text View - ClinicalTrials.gov. Accessed August 19, 2022. https://clinicaltrials.gov/ct2/show/NCT05053035
26.TPN-101 | ALZFORUM. Accessed August 19, 2022. https://www.alzforum.org/therapeutics/tpn- 101
27. Transposon Therapeutics, Inc. A Phase 2a Study of TPN-101 in Patients With Amyotrophic Lateral Sclerosis (ALS) and/or Frontotemporal Dementia (FTD) Associated With Hexanucleotide Repeat Expansion in the C9orf72 Gene (C9ORF72 ALS/FTD). clinicaltrials.gov; 2022. Ac-cessed August 17, 2022. https://clinicaltrials.gov/ct2/show/NCT04993755
28. Kerk SY, Bai Y, Smith J, et al. Homozygous ALS-linked FUS P525L mutations cell- autonomously perturb transcriptome profile and chem-oreceptor signaling in human iPSC microglia. Stem Cell Rep. 2022;17(3):678-692. doi:10.1016/j.stemcr.2022.01.004
29. ION363 | ALZFORUM. Accessed August 19, 2022. https://www.alzforum.org/therapeutics/ion363 30. Ionis Pharmaceuticals, Inc. A Phase 1-3 Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Intrathecally Administered ION363 in Amyo-trophic Lateral Sclerosis Patients With Fused in Sarcoma Mutations (FUS-ALS). clinicaltrials.gov; 2022. Accessed August 18, 2022. https://clinicaltrials.gov/ct2/show/NCT04768972
31. PhD LF. Engensis (VM202) - ALS News Today. Accessed August 19, 2022. https://alsnewstoday.com/vm202/
32. Helixmith Co., Ltd. A 6-Month Extension Study Following Protocol VMALS-002-2 (A Phase 2a, Double-Blind, Randomized, Place-bo-Controlled, Multicenter Study to Assess the Safety of Engensis in Participants With Amyotrophic Lateral Sclerosis). clinicaltrials.gov; 2022. Accessed August 18, 2022. https://clinicaltrials.gov/ct2/show/NCT05176093 33. Safety of Engensis in Participants With Amyotrophic Lateral Sclerosis - Full Text View - ClinicalTrials.gov. Accessed August 19, 2022. https://clinicaltrials.gov/ct2/show/NCT04632225
34. Biogen. A phase 1, safety, tolerability, and distribution study of a microdose of radiolabeled BIIB067 co-administered with BIIB067 to healthy adults. ClinicalTrials.gov Identifier: NCT03764488. Updated Jul 19, 2021. Accessed Mar 1, 2022. https://clinicaltrials.gov/ct2/show/NCT03764488.
35. Ionis Pharmaceuticals Inc. A phase 1, double-blind, placebo-controlled, dose-escalation study of the safety, tolerability, and pharmacokinet-ics of ISIS 333611 administered intrathecally to patients with familial amyotrophic lateral sclerosis due to superoxide dismutase 1 gene muta-tions. ClinicalTrials.gov Identifier: NCT01041222. Updated Apr 13, 2012. Accessed Mar 1, 2022. https://clinicaltrials.gov/ct2/show/NCT01041222.
36. Messina S, Sframeli M. New treatments in spinal muscular atrophy: Positive results and new challenges. J Clin Med. 2020;9(7):2222. doi:10.3390/jcm9072222.