Day Two

• Adeno-associated viral vectors offer the potential of a one-time treatment targeting mutant genes or disease-critical pathways
• Delivery of any genetic medicines to the brain must address multiple challenges. This presentation will address issues of target choice, cell-specific expression, entry across the blood/CSF-brain barriers and dose-related toxicity for AAV capsids

NEW DATA

Explore whether implantable devices and intrathecal delivery approaches can offer meaningful advantages over systemic strategies for CNS targeting, and identify if they are practical, scalable, and still clinically justified

• Identify when device-mediated CNS delivery outperforms systemic or ligand-based approaches
• Debate whether implantation confines this strategy to rare diseases and how engineering and reimbursement innovations could expand use
• Examine key variables that control distribution and reliability including reservoir stability, catheter design, flushing volume, CSF flow, and posture
• Assess trade-offs between device access using minimally modified oligos and complex chemical modification or conjugation strategies

• Exploring targeted strategies for precision delivery, focusing on how route of administration (local/systemic), intracellular trafficking, and endosomal sequestration constrain the translation of oligonucleotide exposure into functional potency
• Preclinical in vivo proof-of-concept data establish a mechanistic framework linking oligonucleotide exposure, endosomal escape, and productive target engagement, independent of target organ or tissue 
• Positioning delivery and endosomal escape as central bottlenecks, we discuss emerging mechanistic insights and translational considerations relevant to CNS-directed applications, emphasizing targeted approaches that improve on-target intracellular availability

NEW DATA

• Evaluate strategies to preferentially deliver oligonucleotides to neurons compared with glial populations to maximise pharmacodynamic impact and therapeutic precision
• Discover how lipid conjugates, peptides, and other targeting modalities modulate intracellular trafficking, regional CNS distribution, and cell specific internalization
• Measure tissue and cellular exposure early in preclinical studies to distinguish effects driven by chemistry from those driven by target biology and guide rational design for selective CNS engagement

• Development of VO659: outlining the path from candidate selection through IND-enabling activities and entry into Phase 1/2a studies
• Broader implications of the VO659 program for advancing next-generation oligo therapies targeting CNS disorders
• Beyond VO659: innovating ASO chemistry to improve CNS uptake

• Achieving deep brain oligonucleotide exposure while managing acute and chronic neurotoxicity
• The role of imaging and PK/PD modelling in optimising CNS dosing strategies
• Limitations of transferrin receptor-mediated delivery and emerging alternative shuttle approaches
• Balancing regional coverage, cell-type specificity, and peripheral exposure risks
• Translational and safety considerations impacting clinical development and regulatory confidence

• Strategies to identifying emerging genetic targets beyond the crowded IP space and evaluating their therapeutic potential with different oligonucleotide modalities
• Overcoming preclinical translation challenges by leveraging humanized and disease-specific models to confirm target relevance, address species-specific phenotypes, and predict clinical efficacy
• Integrating bioinformatics and AI-driven approaches to prioritise causal targets, enhance mechanistic validation, and accelerate the selection of disease-relevant candidates 

NEW DATA

• Strategies to identify emerging genetic targets beyond the crowded IP space and evaluating their therapeutic potential with different oligonucleotide modalities
• Overcoming preclinical translation challenges by leveraging humanized and disease-specific models to confirm target relevance, address species-specific phenotypes, and predict clinical efficacy
• Integrating bioinformatics and AI-driven approaches to prioritise causal targets, enhance mechanistic validation, and accelerate the selection of disease-relevant candidates  

NEW DATA