Antisense Oligonucleotide Therapeutics for Neurodegenerative Disorders

Expanding therapeutic targets from proteins to RNAs opens up new possibilities for neurodegenerative disorders therapeutics development. Recently, a disease-modifying antisense oligonucleotide (ASO) agent was approved for spinal muscular atrophy, suggesting ASOs will fulfill their early promise and become a significant new therapeutic category for neurodegenerative disorders. ASOs are in human subjects testing for Huntington disease, monogenic forms of amyotrophic lateral sclerosis, Alzheimer disease, myotonic dystrophy, Leber congenital amaurosis, Usher syndrome, and retinitis pigmentosum, with many more in preclinical development. Current ASO strategies encompass RNA processing modulation, and RNA target breakdown. Broad ASO mechanism categories are protein restoring versus protein lowering. Individual ASO mechanisms of action range from mutation-specific to impacting many proteins. Current ASOs show great promise in neurodegenerative disorders. Specific ASO designs and mechanisms may be more tenable in this disease area. Preclinical development is already leveraging early knowledge from these initial clinical trials to develop novel ASO cocktails, new ASO chemical modifications, and new ASO RNA and protein targets.