Main Conference Day 3Thursday, 13 November 2025 - CET (Central European Time, GMT+01:00)

Small interfering RNAs are a promising therapeutic modality as they can be designed to target any gene and can be delivered via endocytosis of cell surface receptors. To date, a variety of receptor targeting strategies have been employed, including the addition of sugars or conjugation to artificial ligands, Fc fragments, monoclonal antibodies, and Centyrins. Despite advances in drug targeting, a key challenge in siRNA delivery is ensuring that the drug not only reaches the target cell and is internalized, but also escapes from the endo-lysosome pathway for RISC loading in the cytoplasm. Here we describe how cell activation by Interferon gamma, which we have termed “priming,” increases the potency of multiple receptor-targeted siRNA conjugates by promoting endosomal escape, and we suggest indications for which siRNA therapeutics may be most effective.

Delivering oligonucleotides using protein-based conjugates represents a promising advancement in both oligonucleotide and protein therapeutics. However, these conjugates present significant challenges in synthesis, analytical characterization, and scale-up due to their inherent structural and chemical complexity. This presentation outlines chemistry-driven strategies to address these challenges. We highlight how a focus on conjugate properties and reaction chemistry enabled the elimination of multiple unit operations and chromatography steps, facilitating rapid scale-up to GLP-grade material. We also demonstrate how advanced analytical techniques, particularly mass spectrometry, can differentiate activity based on the site of conjugation. Additionally, we show how rational linker design impacts critical properties such as oligo-to-protein ratios. Our study highlights the importance of integrating chemistry, bioconjugation, and advanced analytical capabilities to support optimization and scale-up of complex oligonucleotide-protein conjugates.

This presentation will provide a review of the clinical advancements of Avidity's antibody-oligonucleotide conjugate programs.

Ethris, a clinical stage biotechnology company, uses proprietary, spray-dryable, clinically validated, non-immunogenic messenger RNA (SNIM®RNA) and lipidoid nanoparticle (SNaP LNP®) technology platforms to discover, design, and develop innovative therapies and vaccines including mucosal vaccines. ETH47 is a first-in-class mRNA-based treatment for uncontrolled asthma patients that was uniquely designed to be administered through a nasal spray. The mRNA contained in ETH47 encodes interferon lambda (IFNλ), a protein crucial for innate immune defense in the airways. ETH47’s versatile, virus- and mutation-independent mode of action has the potential to broadly address seasonal and emerging viral triggers of asthma exacerbations, one of the most common causes of acute symptoms in patients with asthma. ETH47 demonstrated favorable safety and tolerability at all tested doses in a Phase 1 clinical trial in healthy volunteers. The trial confirmed targeted activity in the respiratory tract, with robust local induction of IFNλ and activation of antiviral genes, with no systemic exposure to mRNA, IFNλ, or the lipidoid nanoparticle, thereby minimizing the risk of off-target effects. Ethris is now embarking on a Phase 2 clinical trial that will assess the ability of intranasal ETH47 to reduce asthma-related symptoms, following a rhinovirus challenge in adults with asthma.

mRNA vaccines have demonstrated significant promise in rapidly addressing emerging pandemics due to their swift development timelines, strong efficacy, and favorable safety profiles. However, current delivery technologies present notable limitations, including the need for multidose vials, demanding cold storage conditions, variable biodistribution, and reactogenicity concerns often associated with polyethylene glycol (PEG). To be competitive with other modalities within the established pharmaceutical market, mRNA technology must overcome these hurdles. Optimizing the lipid nanoparticle (LNP) components and the underlying manufacturing technology is key. Here, we present a novel LNP platform developed to directly address these obstacles. Our approach leverages proprietary ionizable lipids, innovative helper lipids, PEG alternatives, and advanced formulation technology to mitigate issues of stability, storage, and reactogenicity. This tailored LNP system is designed to support both prophylactic and therapeutic mRNA vaccines, offering enhanced stability at refrigerated or even ambient temperatures, improved safety profiles, and more flexible dosing formats. Stable, accessible mRNA products will be pivotal for fulfilling the broader potential of this transformative technology.

Oligonucleotides (ONs) have been established as a transformative class of therapeutics over recent decades. ProQR is advancing a highly versatile next generation of RNA base editing technology called Axiomer. This platform leverages Editing Oligonucleotides (EONs) to recruit endogenous ADAR (Adenosine Deaminase Acting on RNA) for precise single nucleotide edits to correct, modulate, or alter RNA and/or protein to help prevent or treat diseases. Based on the pipeline built from Axiomer, this presentation will review optimization of the platform and progress toward future therapeutic applications in the liver and CNS.