Current therapy in amyotrophic lateral sclerosis (ALS): A review on past and future therapeutic strategies

Area of Science:

• Neuroscience
• Pharmacology
• Biochemistry

Background:

• Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease impacting motoneurons (MNs), leading to progressive muscle weakness, paralysis, and death.
• The precise etiology of ALS remains largely unknown, complicating treatment development.
• Current FDA-approved treatments, riluzole and edavarone, offer limited efficacy and no cure for ALS.

Purpose of the Study:

• To provide a comprehensive overview of the multifaceted pathomechanisms implicated in ALS pathogenesis.
• To review recent discoveries and preclinical characterization of novel neuroprotective compounds for ALS.
• To analyze the reasons behind clinical trial failures and propose future therapeutic strategies for ALS.

Main Methods:

• Literature review of ALS pathogenesis pathways, including protein aggregation, excitotoxicity, oxidative stress, mitochondrial dysfunction, apoptosis, and inflammation.
• Survey of recent preclinical studies on neuroprotective compounds targeting these pathways.
• Analysis of clinical trial data and outcomes for ALS therapeutics.
• Discussion of drug combination strategies and alternative therapeutic modalities.

Main Results:

• Multiple molecular and cellular pathways contribute to ALS pathogenesis.
• Numerous neuroprotective compounds have shown promise in preclinical studies.
• Drug combination therapies and alternative approaches are under investigation.
• Clinical failures in ALS drug development are often attributed to complex disease biology and trial design.

Conclusions:

• Despite challenges, ongoing research into specific pathomechanisms offers hope for developing effective ALS treatments.
• Targeting multiple pathways and exploring drug combinations may improve therapeutic outcomes.
• Understanding the reasons for clinical failure is crucial for designing future successful ALS clinical trials.