Expanding therapeutic opportunities for neurodegenerative diseases: A perspective on the important role of phenotypic screening.

Over the last 20 years, there have been remarkably few FDA-approved first-in-class drugs for neurodegenerative diseases. Debilitating conditions such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis have no effective disease-modifying therapeutics on the market, signifying an area of high unmet medical need where novel approaches are needed. Using a phenotypic screening approach, two separate groups discovered small molecule non-antisense oligonucleotide splice modulators for spinal muscular atrophy, a severe monogenetic disease that causes the degeneration ofalpha motor neuronsin the spinal cord. These compounds function by a novel mechanism: selective stabilization of the interaction of U1 small nuclear ribonucleic protein (snRNP), a core component of the spliceosome, with the 5' splice site of a pre-mRNA. The ability of the phenotypic screening approach to uncover a previously unknown mechanism and reveal a new druggable target class has broader implications for other neurodegenerative diseases.