ASOs

ASOs, or antisense oligonucleotides, are short synthetic strands of nucleic acids designed to bind specifically to target RNA sequences. By pairing with their RNA targets, they can modify gene expression through different mechanisms, making them useful as therapeutic agents in a range of diseases.

The primary modes of action include RNase H–mediated degradation of the target RNA, splice-switching to alter pre-mRNA splicing, and steric blocking of translation or microRNA function. Depending on the design, an ASO can promote degradation of disease-causing transcripts, modify the inclusion or exclusion of exons to restore functional protein, or prevent the production of harmful proteins.

Chemistry and design: ASOs employ various backbone chemistries and sugar modifications to enhance stability, affinity, and tolerability. Common backbones include phosphorothioates and phosphodiesters, as well as morpholino (PMO) and peptide nucleic acid (PNA) analogs. Modifications such as 2'-O-methyl, 2'-O-maboron (MOE), and locked nucleic acids (LNA) improve binding to RNA and protect from nuclease degradation. These designs aim for high target specificity while reducing off-target effects and immune activation.

Delivery and administration: The delivery of ASOs is influenced by tissue and disease. CNS targets often require intrathecal administration, while systemic targets may be approached with subcutaneous or intravenous routes. Local delivery is used for ocular and certain muscular targets. Dosing regimens are typically chronic and require ongoing administration.

Applications and status: Several ASOs have reached clinical use, including nusinersen for spinal muscular atrophy, eteplirsen for Duchenne muscular dystrophy, mipomersen for homozygous familial hypercholesterolemia, and inotersen for hereditary transthyretin-mediated amyloidosis. Regulatory outcomes vary, with approvals, safety concerns, and ongoing trials guiding development. Safety considerations include injection-site reactions, thrombocytopenia, liver effects, and potential off-target effects.