Hassan H. Fakih

This workshop examines the mechanistic and translational determinants of intrathecal siRNA delivery in CNS disorders. While achieving broad exposure from CSF is increasingly feasible, translating this into effective and uniform gene silencing across brain region, particularly in deep structures, remains a central challenge. Using non-human primate datasets, crossspecies comparisons, and exposure–response frameworks, this session will explore whether emerging delivery strategies can overcome anatomical and pharmacokinetic barriers in CNS tissues.

Highlights Include:

• Dissecting the distribution of siRNA from CSF into cortical versus deep brain structures, including physical and molecular factors influencing penetration and spatial heterogeneity
• Distinguishing gross tissue exposure from functional intracellular uptake across CNS regions
• Exploring how delivery efficiency influences tissue retention, clearance dynamics, and durability of knockdown
• Discussion on acute tolerability signals, concentrationdependent toxicity, and whether improved efficiency can shift effective dose ceilings
• Evaluating whether current and emerging intrathecal siRNA strategies are sufficient for diseases affecting subcortical structures