Antisense Oligonucleotides: Translation from Mouse Models to Human Neurodegenerative Diseases

Multiple neurodegenerative diseases are characterized by single-protein dysfunction and aggregation. Treatment strategies for these diseases have often targeted downstream pathways to ameliorate consequences of protein dysfunction; however, targeting the source of that dysfunction, the affected protein itself, seems most judicious to achieve a highly effective therapeutic outcome. Antisense oligonucleotides (ASOs) are small sequences of DNA able to target RNA transcripts, resulting in reduced or modified protein expression. ASOs are ideal candidates for the treatment of neurodegenerative diseases, given numerous advancements made to their chemical modifications and delivery methods. Successes achieved in both animal models and human clinical trials have proven ASOs both safe and effective. With proper considerations in mind regarding the human applicability of ASOs, we anticipate ongoing in vivo research and clinical trial development of ASOs for the treatment of neurodegenerative diseases. In this review, Schoch and Miller describe the preclinical research that is developing and has advanced the application of antisense oligonucleotides (ASOs) to human clinical trials for neurodegenerative diseases. Recent clinical successes are highlighted and support the use of ASOs as a viable therapeutic strategy.