Amyotrophic lateral sclerosis: exploring pathophysiology in the context of treatment

Abstract

Amyotrophic lateral sclerosis (ALS) is a complex, neurodegenerative disorder in which alterations in structural, physiological, and metabolic parameters act synergistically. Over the last decade there has been a considerable focus on developing drugs to slow the progression of the disease. Despite this, only four disease-modifying therapies are approved in North America. Although additional research is required for a thorough understanding of ALS, we have accumulated a large amount of knowledge that could be better integrated into future clinical trials to accelerate drug development and provide patients with improved treatment options. It is likely that future, successful ALS treatments will take a multi-pronged therapeutic approach, targeting different pathways, akin to personalized medicine in oncology. In this review, we discuss the link between ALS pathophysiology and treatments, looking at the therapeutic failures as learning opportunities that can help us refine and optimize drug development.

Keywords:

• Genetics
• glutamate excitotoxicity
• mitochondria
• oxidative stress
• therapeutics

Acknowledgments

Medical writing assistance for this manuscript was provided by KTP (Knowledge Translation Partners), Montreal, Canada. Amylyx supported the medical writing assistance for this manuscript.

Declaration of interest

In accordance with Taylor & Francis policy and my ethical obligation as a researcher, I am reporting that I, Dr Angela Genge have received funding from the following companies: Alexion, Als-Pharma, Amicus Therapeutics, Amylyx, Anelixis, Anexon, Apellis, Atlantic Research Group, Biogen, Calico, Cytokinetics, Eli Lilly, Ionis, Medtronic, Mitsubishi Tanabe Pharma, Orion, QurAlis, RA Pharma, Roche, Sanofi Genzyme, UCB, Wave Life Therapies. I am also a paid consultant for Amylyx Pharmaceuticals, and CMO for Quralis. I have disclosed these interests fully to Taylor & Francis, and I have in place a plan for managing any potential conflicts arising from these disclosures.

In accordance with Taylor & Francis policy and my ethical obligation as a researcher, I am reporting that I, Dr Steven Wainwright am an employee of Amylyx Pharmaceuticals. As a full-time employee of Amylyx Pharmaceuticals, I may have stock option ownership in Amylyx Pharmaceuticals, Inc.

In accordance with Taylor & Francis policy and my ethical obligation as a researcher, I am reporting that I, Dr Christine Vande Velde have consulted for Amylyx and BridgeBio, and am partnered with Novation Pharmaceuticals on Target ALS and DOD funded projects. I am also the Scientific Director of the Robert Packard Center for ALS Research.