Antisense Oligonucleotide Therapy for the Nervous System: From Bench to Bedside with Emphasis on Pediatric Neurology

Antisense oligonucleotides (ASOs) are disease-modifying agents affecting protein-coding and noncoding ribonucleic acids. Depending on the chemical modification and the location of hybridization, ASOs are able to reduce the level of toxic proteins, increase the level of functional protein, or modify the structure of impaired protein to improve function. There are multiple challenges in delivering ASOs to their site of action. Chemical modifications in the phosphodiester bond, nucleotide sugar, and nucleobase can increase structural thermodynamic stability and prevent ASO degradation. Furthermore, different particles, including viral vectors, conjugated peptides, conjugated antibodies, and nanocarriers, may improve ASO delivery. To date, six ASOs have been approved by the US Food and Drug Administration (FDA) in three neurological disorders: spinal muscular atrophy, Duchenne muscular dystrophy, and polyneuropathy caused by hereditary transthyretin amyloidosis. Ongoing preclinical and clinical studies are assessing the safety and efficacy of ASOs in multiple genetic and acquired neurological conditions. The current review provides an update on underlying mechanisms, design, chemical modifications, and delivery of ASOs. The administration of FDA-approved ASOs in neurological disorders is described, and current evidence on the safety and efficacy of ASOs in other neurological conditions, including pediatric neurological disorders, is reviewed.