Explore the Agenda
8:00 am Check-In, Coffee & Light Breakfast
siRNA Track
9:00 am Workshop A: Intrathecal siRNA in the CNS: Distribution Gradients, Functional Uptake & Dose Ceiling Reality
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
ASO Track
9:00 am Workshop B: ASO Discovery Under Pressure: Potency, Sequence Selection & Dose Considerations in CNS
This workshop will explore how teams approach potency, sequence selection, and dosing considerations when advancing antisense oligonucleotides for CNS applications. Given the long tissue half-life and dosing requirements often associated with CNS delivery, early discovery decisions can have important implications for clinical strategy, safety, and manufacturability. The session will focus on how different organizations define and balance potency, tolerability, and feasibility, and whether there are emerging best practices in early screening and candidate selection that support successful translation.
Highlights Include:
- Discussion around how teams define and interpret sufficient knockdown in vitro and in vivo, and how this informs progression decisions
- Exploring challenges in identifying accessible and functionally relevant transcript regions
- Examining how potency influences dose levels, delivery strategy, and overall development considerations in CNS settings
- Considering how sequence-dependent off-target effects are evaluated and incorporated into early decision-making
- Reflecting on whether there are opportunities to evolve screening paradigms and selection criteria to better support downstream success
12:00 pm Lunch
1:00 pm Workshop C: CNS siRNA Chemistry & Conjugation Architecture: Duplex Design, 2 Modifications & Delivery Constructs
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?
1:00 pm Workshop D: Splice Modulation, Steric Block & Gain-of-Function Design: Where ASOs Retain a Mechanistic Advantage
This workshop interrogates transcript-level engineering using ASOs, including splice-site modulation, exon inclusion/exclusion control, and regulatory element targeting in mutation-driven CNS disease. Rather than reducing transcript levels, these strategies aim to reshape RNA processing, restore functional protein output, or rebalance isoform expression. The session will examine sequence dependency, structural constraints, and translational durability considerations that define success in nondegradative ASO programs.
Highlights Include:
- When is splice modulation superior to transcript knockdown in CNS disease?
- How do steric-block ASOs achieve durable functional rescue without transcript degradation?
- What are the discovery constraints in identifying effective splice-switching sequences?
- Can gain-of-function ASOs reduce dose burden relative to knockdown strategies?