Jimmy Weterings
Vice President & Head of Oligonucleotide Therapeutics Bonito Bioscience
Jimmy Weterings, PhD is Senior Director, Head of Technology Development at Sirnaomics, USA.
Jimmy has had a tight bond with Oligonucleotides since 2002, performing research on PNA (conjugates) in the van Boom group at Leiden University, the Netherlands and targeted SSO conjugates at Prosensa. During his Ph.D at Leiden University he synthesized and studied CpG Oligonucleotide and other TLR ligand containing conjugates. At Cenix BioScience, he developed targeted siRNA conjugates for CNS delivery. And at Cristal Therapeutics he led various projects on the (targeted) nanomedicine delivery of oligonucleotide in oncology. In 2019 he joined AstraZeneca in Sweden, to further the advancement of (targeted) oligonucleotide therapeutics. Since December 2022, Jimmy joined Sirnaomics in the USA as Senior Director, designing novel oligonucleotide chemistries and targeted versions thereof.
Jimmy (co-)authored 13 articles and holds several patents for drug delivery enabling technologies, including the most recent one on TMTHSI, ClicR® exclusively licensed to Synaffix and commercially available for R&D purposes.
Seminars
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?
- Evaluating whether receptor-mediated conjugation strategies provide a translational advantage over intrinsic chemistry optimization, given the absence of a validated receptor–ligand specific to CNS
- Examining the structural and operational complexity introduced by antibody–oligonucleotide constructs and the requirement for highly efficient delivery at low systemic doses to avoid toxicity risk
- Debating whether emerging alternatives or intrinsic chemistry tuning remains the more scalable and practical strategy for CNS programs
- 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
- 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
