Day Two

• Targeted MAPT Silencing via Brain Shuttle–Enabled siRNA Delivery in Alzheimer’s Disease
• Optimising CNS delivery of therapeutic payloads using TXP1, a novel second‑generation, brain‑selective shuttle engineered for enhanced transcytosis across the BBB
• Identifying a potent MAPT‑targeting oligonucleotide for tau silencing and optimising its site‑specific conjugation to TXP1 to enable efficient CNS delivery and robust knockdown
• Demonstrated in vivo efficacy, with potent MAPT knockdown observed in a PoC study in transgenic mice following intravenous administration of TXP1‑MAPT

• 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

• Evaluate strategies to achieve robust oligonucleotide penetration into deep brain regions while maintaining controlled CNS distribution
• Examine approaches to enhance neuron-specific uptake over glial populations, improving cell-type precision and therapeutic impact
• Assess the limitations of current delivery systems, including transferrin receptor-mediated approaches, and discuss emerging shuttle technologies for deeper and more targeted brain access
• Leverage imaging and PK/PD modelling to quantify regional and cell-specific exposure, enabling early differentiation between delivery efficiency and target biology
• Address safety and translational considerations, balancing deep CNS exposure, cell selectivity, and risks of neurotoxicity and peripheral off-target effects

• 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

• A novel RNA splicing modulation platform that selectively activates pseudo-exons to precisely control gene and protein expression at the source of disease
• Targeted oligonucleotides function as an innovative molecular switch, displacing repressive RNA-binding proteins to enable pseudo-exon inclusion during splicing, deliberately altering mRNA and downstream protein production
• Powered by a proprietary map spanning over 90% of spliced protein-coding genes with pseudo-exons, the platform unlocks a vast therapeutic targeting space with broad applicability across many conditions

• Aerska is developing siRNAs for CNS indications
• Aerska’s lead program is APP Program for the treatment of Alzheimer’s Disease
• Aerska will be presenting their approach in siRNA lead development to identify a potent sequence and the delivery strategy to reach CNS

• 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

• Evaluate whether implantable and intrathecal delivery offer clear advantages over systemic approaches for CNS targeting
• Identify when device-based delivery outperforms systemic or ligand-mediated strategies
• Debate whether implantation limits use to rare diseases and how innovation could broaden applicability
• Examine key factors impacting distribution and reliability, including reservoir stability, catheter design, CSF flow, and dosing parameters
• Assess trade-offs between device-enabled delivery of simpler oligos and more complex chemical or conjugation strategies

• 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

• Explore the search for CNS-targeted oligonucleotide ligands and shuttle strategies that could match GalNAc’s efficiency in the liver
• Evaluate emerging chemistry, conjugation, and receptor-mediated approaches, including methods to validate and optimize chemical modifications for CNS delivery
• Discuss translational opportunities and challenges in creating next-generation CNS delivery platforms that enable differentiated therapeutic strategies

NEW DATA