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

• Evaluating intracellular sequestration of oligonucleotides in endosomes and uptake by glial or immune cells to understand limitations in target neuron bioavailability
• Exploring ligand and conjugate strategies, including lipid, peptide, and antibody modifications, to improve endosomal escape and cytosolic delivery
• Linking escape efficiency to dosing, safety, and disease-specific biology to optimise therapeutic index across neuro targets

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 and clinical positioning of VO659, outlining the path from candidate selection through IND-enabling activities and entry into Phase 1/2a studies
• Translational strategies used to bridge preclinical pharmacology, safety, and target engagement with early clinical trial design in Huntington’s disease
• Broader implications of the VO659 program for advancing next-generation oligo therapies targeting CNS disorders

• 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