This workshop explores the structural engineering challenges unique to CNS siRNA programs, where duplex chemistry, 2 modifications, phosphorothioate content, and conjugation strategy collectively determine intracellular delivery and translational feasibility. Discussions of complex multi-component constructs incorporating linkers and antibodies and introducing additional PK, DAR, and manufacturability considerations.

Highlights Include:

• Is there an optimal duplex architecture for CNS exposure and sustained knockdown?
• How should DAR be optimized in CNS shuttle systems?
• Discussion will examine whether single- versus multi-payload conjugation improves exposure or increases structural complexity and manufacturing risk
• Where and when should linker cleavage occur for effective intracellular release?
• How does premature cleavage versus delayed release affects systemic sink and CNS bioavailability?