Genetic Therapies Bootcamp: Foundations, Frontiers, and Clinical Engagement OnDemand-03-10 14-15 318-323 Yu Session 2 ASOs

Video Transcription

Video Summary

Dr. Yu provides an in-depth overview of antisense oligonucleotides (ASOs), short chemically modified RNA strands designed to modulate gene expression. ASOs either correct mis-splicing to boost gene expression or recruit RNAse H to degrade target RNA, thus down-regulating gene expression. Their simple, customizable manufacturing process, based on a 1984 chemical synthesis method, allows rapid development and relatively low cost (~$40,000) per drug. ASOs are chemically stabilized via backbone modifications (phosphorothioates) and nucleotide alterations (e.g., 2'-O-methylation) and include variants like phosphomorpholinos.<br /><br />Clinically, ASOs have found success mainly in neurological diseases, exemplified by FDA-approved drugs like nusinersen for spinal muscular atrophy and tofersen for SOD1-ALS. ASOs' easy CNS delivery via intrathecal injection enables broad brain and spinal cord uptake. The field has evolved from early disappointments to pioneering "N-of-1" personalized therapies, such as the Mielisyn program targeting rare mutations in CLN7 Batten disease patients. Dr. Yu shares case studies demonstrating sustained clinical benefit and molecular rescue in patients with ataxia telangiectasia and KCNT1 neonatal epilepsy, though side effects like hydrocephalus highlight dosing challenges.<br /><br />Overall, ASOs represent a flexible, precise, and increasingly practical therapeutic platform, especially for genetic neurological disorders, with expanding FDA support and rising individualized treatment applications. Collaborative efforts aim to standardize development and interpretation of variants for broader, equitable clinical use.

Keywords

antisense oligonucleotides

gene expression modulation

phosphorothioates

neurological diseases

FDA-approved ASO drugs

intrathecal CNS delivery

personalized genetic therapies