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

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.

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting motor neurons. In their Review, Shaw and colleagues provide a comprehensive picture of the various pathological mechanisms involved in this complex disease, and discuss the deep and diverse pipeline under development to tackle these processes. They highlight advances in ALS translational research that might be broadly applicable to other neurodegenerative disorders.

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.