A chemogenomic approach seems indispensable for effective treatment of
amyotrophic lateral sclerosis
Abstract
ALS is a fatal untreatable disease involving degeneration of motor
neurons. Μultiple causative genes encoding proteins with versatile
functions have been identified indicating that diverse biological
pathways lead to ALS. Gene and stem cell-based therapies are not
expected to enter clinical practice anytime soon. Thus, chemical
entities represent a promising choice to delay ALS progression,
attenuate symptoms and/or increase life expectancy. Various compounds
proved effective in transgenic models overexpressing distinct ALS
causative genes but showed no efficacy in clinical trials. Notably,
while animal models provide a uniform genetic background for preclinical
testing, ALS patients are not stratified, and the distinct genetic forms
of ALS are treated as a unique group which could explain the discrepancy
between treating genetically homogeneous mice and quite heterogeneous
patient cohorts. We suggest that chemical entity-genotype correlation
should be exploited to guide patient stratification for therapy.