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  • Review Article
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Amyotrophic lateral sclerosis: a neurodegenerative disorder poised for successful therapeutic translation

Nature Reviews Drug Discovery volume 22, pages 185–212 (2023)Cite this article

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Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating disease caused by degeneration of motor neurons. As with all major neurodegenerative disorders, development of disease-modifying therapies has proven challenging for multiple reasons. Nevertheless, ALS is one of the few neurodegenerative diseases for which disease-modifying therapies are approved. Significant discoveries and advances have been made in ALS preclinical models, genetics, pathology, biomarkers, imaging and clinical readouts over the last 10–15 years. At the same time, novel therapeutic paradigms are being applied in areas of high unmet medical need, including neurodegenerative disorders. These developments have evolved our knowledge base, allowing identification of targeted candidate therapies for ALS with diverse mechanisms of action. In this Review, we discuss how this advanced knowledge, aligned with new approaches, can enable effective translation of therapeutic agents from preclinical studies through to clinical benefit for patients with ALS. We anticipate that this approach in ALS will also positively impact the field of drug discovery for neurodegenerative disorders more broadly.

Key points

  • Amyotrophic lateral sclerosis (ALS), with a lifetime risk of ~1/350, represents an area of huge unmet need and is a useful model of neurodegeneration, with measurable changes in motor function over a relatively short time frame.

  • The field of ALS has advanced significantly over the last decade, with rapid progress in understanding the genetic architecture and the pathophysiological mechanisms of the disease, and in the development of robust, exploitable preclinical model systems.

  • Potential biomarkers of phenotypic conversion, target engagement and therapeutic efficacy have now emerged. Plasma and cerebrospinal fluid (CSF) neurofilament protein levels look particularly promising and may improve the efficiency of future clinical trials and allow identification of responder subgroups.

  • The identification of several biological pathways with the potential to be tackled therapeutically has generated a promising pipeline of preclinical approaches and clinical trials.

  • Genetic therapy trials are now poised for successful translation. In addition, combination therapies or therapies with the potential to ameliorate several pathophysiological mechanisms contributing to motor neuron injury are now being evaluated.

  • Recent innovations in trial design are poised to enhance outcome measures, and patient selection and randomization, while minimizing the impact of disease heterogeneity and increasing statistical power.

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Fig. 1: ALS pathophysiology, genetic causes and risk factors.
Fig. 2: The major ALS pathophysiological targets currently being pursued.
Fig. 3: A rational and enhanced preclinical efficacy screening cascade for ALS.

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Acknowledgements

P.J.S. is supported as an Emeritus NIHR Senior Investigator and by the NIHR Sheffield Biomedical Research Centre (IS-BRC-1215-20017), the Motor Neurone Disease Association (AMBRoSIA MNDA 974-797) the Medical Research Council (MRC COEN 4017), the EU Horizon 2020 programme (H2020-633413) and the My Name’5 Doddie Foundation (DOD/14/43). N.S., P.J.S. and R.J.M. are funded by FightMND Australia (03_DDG_2020_Shan). The authors thank L. Evans for her skilled assistance in the preparation of this manuscript.

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Authors and Affiliations

  1. Sheffield Institute for Translational Neuroscience, Faculty of Medicine, Dentistry and Health, University of Sheffield, Sheffield, UK

    Richard J. Mead & Pamela J. Shaw

  2. Neuroscience Institute, University of Sheffield, Sheffield, UK

    Richard J. Mead & Pamela J. Shaw

  3. Keapstone Therapeutics, The Innovation Centre, Broomhall, Sheffield, UK

    Richard J. Mead & Pamela J. Shaw

  4. Aclipse Therapeutics, Radnor, PA, US

    Ning Shan & H. Joseph Reiser

  5. MSD UK Discovery Centre, Merck, Sharp and Dohme (UK) Limited, London, UK

    Fiona Marshall

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Contributions

R.J.M., N.S. and P.J.S. researched data for the article. All authors contributed substantially to discussion of the content. R.J.M., N.S. and P.J.S. wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Pamela J. Shaw.

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Competing interests

R.J.M. is cofounder of and holds shares in Keapstone Therapeutics, collaborates and receives funding from BenevolentAI, Quell Therapeutics, Sosei Heptares and MSD, is a consultant to Aclipse Therapeutics, has shares in Aclipse One Inc and is an inventor on patents related to M102. N.S. is an employee and shareholder of Aclipse Therapeutics. H.J.R. is the chairman of the Board of Aclipse Therapeutics. F.M. is an employee and shareholder of Merck and Co. P.J.S. is an advisory board member and consultant for Biogen, Aclipse Therapeutics, Quell Therapeutics, BenevolentAI, QurAlis, Astex, GeniUS and Eli Lilly and collaborates with and receives research funding from Quell Therapeutics, Aclipse Therapeutics, Pfizer and SwanBio. She is a cofounder of and holds shares in Keapstone Therapeutics and holds shares in Aclipse One Inc. She is an inventor on patents related to low-dose IL-2, SRSF1 and M102. Support for clinical trials participation in the last five years has been received from Biogen, Alexion, Orion Pharma, WAVE, the EU Horizon 2020 programme and UK NIHR.

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Supplementary information

Glossary

Cryptic exon

An exon that is not normally included in the final mRNA transcript of a gene but which can be included under certain circumstances such as mutations elsewhere in the gene, changes in the state of the cell or loss of factors that normally regulate exon splicing.

DNA damage response

The process by which cells maintain genomic integrity in the face of continuous mutation-causing insults. It comprises both DNA repair mechanisms and cell-cycle checkpoint regulation.

Embedded experimental medicine approach

Incorporation of multiple readouts of a biological mechanism related to the therapeutic approach being tested within a clinical trial in order to understand the impact of the therapeutic agent on disease processes.

Heat shock response

A rapid cellular response to stress that increases, usually via transcriptional activation, the availability of molecular chaperones to enable cytoprotection.

Inflammasome

Multiprotein complex of innate immune receptors which are required for activation of inflammatory responses and specifically lead to maturation and secretion of IL-1β and IL-18.

Proteinopathy

The accumulation of a specific protein, either the wild-type or a mutant variety, in excess with altered conformations that facilitate aggregation.

Rasch model

A mathematical framework against which test developers can compare empirical data to assess an instrument’s capacity to emulate the properties of fundamental measurement (invariance and unidimensionality) and thus serve as a tool for quantifying unobservable human conditions.

Repeat-associated non-AUG (RAN) translation

The initiation of protein translation in the absence of a classic AUG start codon in the RNA species being translated. It is often associated with GC-rich repetitive sequences and can occur in multiple reading frames.

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Mead, R.J., Shan, N., Reiser, H.J. et al. Amyotrophic lateral sclerosis: a neurodegenerative disorder poised for successful therapeutic translation. Nat Rev Drug Discov 22, 185–212 (2023). https://doi.org/10.1038/s41573-022-00612-2

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