Main Conference Day 2 - Europe/Amsterdam
Therapeutic siRNAs require chemical modifications to resist nuclease degradation and achieve durable effects. We identified a modification pattern combining locked nucleic acids (LNA) and phosphorothioate (PS) linkages leveraging their stabilizing effects. LNA at the penultimate position of the duplex region enhances mRNA knockdown efficacy and durability in vivo in mice. This design reduces the required number of PS linkages, thereby lowering stereochemical complexity.
- Lucas Bethge, Ph.D. - VP, Group Leader Chemistry, Silence Therapeutics
Alpha-1 antitrypsin deficiency (AATD) is a genetic disease caused by the PiZ mutation in the SERPINA1 gene, resulting in deficient M-AAT protein and progressive lung and liver damage. AIR-001, an investigational, subcutaneously delivered GalNAc-conjugated oligonucleotide, is designed to precisely correct this mutation at the RNA level. Robust preclinical data demonstrate potent, dose-dependent editing with no off-target effects and durable exposure across multiple model systems. Supported by this compelling preclinical package, AIR-001 has advanced into the Phase 1 RepAIR1 clinical trial, marking a significant milestone for RNA base editing as a therapeutic modality.
- Sriram Sathy, Ph.D. - Chief Scientific Officer, AIRNA
- Jacques Dumas - Chief Scientific Officer, Arrakis Therapeutics
Regulators increasing expect terminal sterilization for ASO drug products by steam/autoclave as a process that offers high sterility assurance levels (≤10-6). Aseptic processing is only allowed if steam sterilization is not feasible. Published ASO data to date (DeCollibus et al 2023) largely focus on molecule-centric, concentration-based chemical degradation, such as depurination and backbone cleavage/hydrolysis, with limited evaluation of the formulation aspects. EMA draft guidance (EMA/CHMP/CVMP/QWP/262313/2024) states that moderate degradation, even above qualification limits, is not enough to reject terminal sterilization. Instead, the guideline encourages optimizing formulation factors (pH, buffer system, and osmolality), and container-closure to enable its use. With advancements in ASO chemical modifications and molecule designs, formulation composition may emerge as a potentially limiting factor. This presentation will illustrate some case studies under such circumstances to help make informed decisions on feasibility of steam sterilization during early phases of ASO drug product development.
- Bhavani Prasad Vinjamuri, Ph.D - Scientist II, Biogen
Posttranslational modifications (PTMs) have a critical role in shaping peptide structure and function. This talk highlights conotoxins as model small, structured bioactive peptides to explore how PTMs influence folding, stability, and biological activity. Insights from these systems inform rational peptide design, and synthesis of modified peptides to understand and harness their biological activities.
- Anne Conibear, BSc(Hons) MSc PhD - Assistant Professor, Peptide and Protein Chemistry, Technische Universität Wien
α-Conotoxin Vc1.1 is a disulfide-rich peptide and a promising drug candidate for treating neuropathic and chronic pain. Backbone cyclisation was applied to enhance its drug-like properties, resulting in improved serum stability and oral bioavailability. However, this modification also adversely affected its stability and activity in simulated intestinal fluid (SIF). To address these adverse effects, we explored the use of polyethylene glycol (PEG) linkers as substitutes for peptide backbone cyclization linkers.
- David Craik, PhD - Professor of Biomolecular Structure, University of Queensland
Radioligand therapy (RLT) employs radioactive atoms linked to targeting peptide-based ligands to deliver radiation directly to cancer cells. In this presentation we will explores the principles of this innovative way of using peptides to treat cancer and also CMC challenges and opportunities.
- John Lopez, PhD - Associate Director Science & Technology, Novartis
- Karunakar (Karu) Sukuru, R.Ph., Ph.D - Global Vice President, Pharma Product Development and Head, Scientific Advisory, Catalent