Day One

•  Assessing whether intrathecal administration is operationally viable for high prevalence CNS populations given procedural burden, treatment infrastructure, and long-term dosing frequency, and whether certain disorders are inherently better suited to intrathecal versus systemic BBB shuttle-based delivery approaches
• Evaluating whether systemic brain shuttle platforms can achieve therapeutically meaningful CNS exposure particularly as programs move from rare to common disease settings
• Examining how expansion into larger indications reshapes manufacturing and competitive dynamics, including oligonucleotide drug substance capacity, cost of goods at commercial scale, multi-vendor CMC complexity for antibody or ligand conjugates, raw material supply constraints for shuttles, and whether manufacturing readiness will ultimately accelerate or hinder competition in the CNS oligo space

• Leveraging antisense oligonucleotides (ASOs) to modulate NaV1.7 expression as a novel non-opioid therapeutic strategy for chronic pain
• Positioning pain as an emerging and underexplored indication for oligonucleotide therapeutics beyond rare genetic and neurodegenerative diseases
• Applying AI and machine learning–enabled approaches to optimize ASO sequence and chemistry selection, improving target engagement and therapeutic index in preclinical development

A prime chance to make the most of in-person networking and forge new connections as new companies enter, and existing ones broaden their presence within CNS oligo drug development space. Designed to maximize your introduction to numerous new individuals and serve as a catalyst for ongoing discussions during the summit.

• Reassessing the limitations of TfR1-mediated delivery including broad peripheral expression, systemic sink effects, tolerability concerns, and limited cell-type specificity and evaluating whether alternative receptors such as CD98, IGF1R, peptide ligands and LNP-enabled formats can deliver improved CNS selectivity
• Examining emerging BBB access strategies, including receptor alternatives and physical modulation approaches such as antibody-mediated opening or focused ultrasound, while balancing enhanced penetration against the biological risks of barrier disruption

• We have developed a TfR1 mediated delivery platform capable of transporting therapeutic oligonucleotides to both muscle and the CNS
• This delivery platform has translated into clinically meaningful functional improvements in neuromuscular diseases, including DMD and DM1
• In the CNS, our approach achieves broad and homogeneous brain distribution of oligonucleotide payloads, reaching deep brain regions that are inaccessible via intrathecal administration
• We have now extended the TfR1 mediated CNS delivery approach to neurological disease targets, demonstrating robust target modulation in non human primates across multiple brain regions, including deep structures such as the caudate and putamen
• These new data highlight the potential of our CNS delivery platform to enable disease modifying therapies for neurodegenerative and other neurological disorders

• Our presentation will focus on our novel approach to non-invasive brain delivery using G-aggregate antisense oligonucleotides
• This technology enables direct CNS targeting without invasive procedures, addressing the critical challenge of blood-brain barrier penetration for oligonucleotide therapeutics
• Our G-rich sequences form stable aggregates that enhance brain uptake and provide nuclear translocation capabilities

• Discussing a novel “Trojan horse” technology that enables the direct delivery of oligos to the brain via intravenous or subcutaneous administration
• Therapeutic efficacy in Huntington’s disease demonstrated at a dose significantly lower than the standard intrathecal ASO dose (less than 1,000 the dose used intrathecally) Over 95% halting of disease progression in chronic preclinical studies
• In a collaboration with a large pharmaceutical company, a single IV dose of an ASO complexed to our Trojan horse was able to achieve equivalent protein reduction as an ICV dose. Confirmed safety and consistent brain delivery in repeat-dose non-human primate studies
• This non-invasive delivery approach offers a significant clinical advantage over invasive modalities or other BBB shuttles and could be a powerful enabler for any siRNA/ASO or peptide/protein programs targeting CNS indications