A chemogenomic approach is required for effective treatment of amyotrophic lateral sclerosis

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with diverse genetic causes.
• Current treatments, including chemical entities and emerging therapies, face challenges in clinical translation.
• Preclinical models often lack the genetic heterogeneity seen in ALS patient populations.

Purpose of the Study:

• To address the discrepancy between preclinical efficacy and clinical trial outcomes in ALS.
• To propose a novel strategy for improving pharmacotherapy in ALS patients.
• To highlight the importance of genetic stratification in ALS treatment development.

Main Methods:

• Review of existing literature on ALS genetics, preclinical models, and clinical trials.
• Analysis of discrepancies between drug efficacy in genetically homogeneous animal models and heterogeneous patient cohorts.
• Proposal for genotype-guided patient stratification for pharmacotherapy.

Main Results:

• Compounds effective in ALS mouse models often fail in human clinical trials.
• ALS patient populations exhibit significant genetic heterogeneity, unlike uniform animal models.
• A lack of patient stratification by genetic background may explain treatment failures.

Conclusions:

• Exploiting genotype-phenotype correlations is crucial for effective ALS pharmacotherapy.
• Stratifying ALS patients based on their genetic background can optimize drug selection.
• Personalized medicine approaches, guided by genetic profiles, hold promise for delaying ALS progression and improving patient outcomes.