Genetic and Mechanistic Insights Inform Amyotrophic Lateral Sclerosis Treatment and Symptomatic Management: Current and Emerging Therapeutics and Clinical Trial Design Considerations

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting both upper and lower motor neurons. ALS is classically characterized by painless progressive weakness, causing impaired function of limbs, speech, swallowing, and respiratory function. The disease is fatal within 2-4 years, often the result of respiratory failure. The pathologic hallmark for a majority of ALS cases is aberrant cytoplasmic accumulations of the nuclear protein TAR-DNA binding protein (TDP-43). A total of 10-15% of ALS can be attributed to a single gene mutation, known as genetic or "familial" ALS, while the remainder of cases are termed nongenetic or "sporadic" although heritability has been measured in up to 37% in this population. Complex interactions between genetics, environment, and physiologic susceptibility are thought to contribute to disease. Management is primarily supportive in nature, though there are several approved treatments worldwide. This review details the mechanisms and evidence of approved disease-modifying treatments, relevant measures to track disease burden and progression used in clinical trials, and approaches to pharmacologic management of common symptoms in ALS. As there is not currently a cure for ALS, research into the complex pathophysiologic and genetic alterations contributing to disease is of great interest. This review further discusses the current understanding of genetic etiologies and altered physiology leading to disease, such as neuroinflammation, integrated stress response, aberrant proteostasis and mitochondrial dysfunction, among others. The translation of preclinical discoveries into current investigational therapeutics, novel therapeutic categories such as antisense oligonucleotides and stem cell transplantation, as well as future horizons harnessing the power of artificial intelligence in drug development and clinical trials are discussed.

Fig. 1

Mechanisms linked to current ALS therapeutics. Sites of action for medications and selected supplements used for the treatment of ALS. Tofersen is limited to patients with SOD1 mutations. ALCAR: acetyl-L-Carnitine; ATP: adenosine triphosphate; EEAT: Excitatory amino acid transporters; HCY: homocysteine; HSP: heat shock protein; MethylCo: methylcobalamin; mRNA: messenger RNA; Mt SOD1: mutant superoxide dismutase 1; ROS: reactive oxidative species; SAM: S-adenosylmethionine. Created in BioRender. Source: Goutman, S. (2025) https://BioRender.com/h74e601

Fig. 2

Therapeutics for the management of ALS symptoms. The mainstay of ALS clinical management is addressing and controlling symptoms. While non-pharmacologic and secondary sources of symptoms should be evaluated at every visit, pharmacologic options are frequently utilized. A range of medications are available to target the diverse symptoms experienced by patients with ALS. Created in BioRender. Source: Goutman, S. (2025) https://BioRender.com/w04b047

Fig. 3

Screening criteria for ALS clinical trials included in final review. ClinicalTrials.gov search strategy to identify current investigational therapeutics in phase 1, 2, and 3 trials for ALS; 211 trials were evaluated and ultimately 60 trials were included in the final review

Fig. 4

ALS therapeutic targets of drugs in phase 1, 2, and 3 clinical trials. ALS drugs in clinical trials currently target multiple pathophysiologic mechanisms implicated in ALS pathogenesis. These mechanisms include impaired proteostasis and integrated stress response within motor neurons; neuroinflammation mediated by microglia, astrocytes, and blood–brain barrier infiltration of peripheral immune cells, such as regulatory T cells (T_regs); oxidative stress mediated by reactive oxygen species (ROS); impaired neuromuscular junction and axonal transport; mitochondrial dysfunction; alterations in RNA metabolism; excitotoxicity due to glutamate-mediated calcium influx into motor neurons; and changes to the gut microbiome. Additionally, use of stem cells and isolated neurotrophic factors are used to stimulate motor neuron growth and survival. Gene-specific therapies, such as antisense oligonucleotides, are also employed to target various ALS pathophysiologic mechanisms, particularly in genetic ALS. Created in BioRender. Source: Goutman, S. (2025) j37l770