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.

Efficient intracellular delivery remains a major barrier to fully realizing the therapeutic potential of RNA-based drugs. While targeted conjugates such as antibody–oligonucleotide formats (AOCs) can improve cellular uptake, a large fraction of the oligonucleotide payload typically remains sequestered in endosomes, limiting therapeutic efficacy. Sapreme’s proprietary SPT platform offers a first-in-class solution: a chemically defined delivery enhancer that enables intrinsic endosomal escape and can be flexibly integrated into a wide range of targeted oligonucleotide conjugates. Here, we present new data in relevant in vitro and in vivo model systems demonstrating the efficacy of antibody-oligonucleotide-SPT-conjugates (AOSCs) for a variety of applications, eg neuromuscular delivery and oncology, and the marked improvement over traditional AOCs.

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 emerged as transformative tools in both prophylactic and therapeutic medicine. Their rapid design and manufacturing enable swift responses to emerging infectious diseases, while their robust efficacy and favorable safety profiles have set new standards for vaccine development. In prophylactic applications, mRNA vaccines offer adaptability to novel pathogens, high immunogenicity, and the potential for scalable production. In therapeutic contexts, especially in oncology, mRNA technology enables the encoding of multiple tumor antigens in a single construct—empowering the immune system to mount a broad and targeted response. Despite these advantages, current delivery platforms—most notably lipid nanoparticles (LNPs)—face significant challenges. These include the need for stringent cold storage, instability in multidose formats, inconsistent biodistribution, and immune reactions linked to excipients such as polyethylene glycol (PEG). Moreover, high-dose and frequent administration, especially in cancer immunotherapy, exacerbates concerns over reactogenicity, anti-PEG antibodies, and off-target effects like liver accumulation. To address these hurdles, we have developed innovative LNP formulations tailored for both prophylactic and therapeutic (oncological) settings: 1) Prophylactic Innovation: Our next-generation LNP platform employs proprietary ionizable lipids, advanced helper lipid compositions, and PEG alternatives. These advances enhance vaccine stability at refrigerated and even ambient temperatures, simplify logistics, and minimize acute immune reactions. This enables the use of mRNA vaccines in broader, real-world scenarios where cold-chain requirements are a barrier; and 2) Oncological (Therapeutic) Innovation: For cancer immunotherapy, we present a PEG-free, liver-bypassing LNP platform optimized for the delivery of multi-epitope mRNA constructs. This design supports repeated, high-dose administrations typical in oncology by reducing reactogenicity and improving biodistribution. Our approach facilitates the induction of potent, broader T cell responses while minimizing off-target effects—key for the efficacy and safety of personalized or off-the-shelf cancer vaccines. By transforming both the prophylactic and therapeutic delivery of mRNA, CureVac’s tailored LNP platforms are designed to overcome current technological barriers—unlocking the promise of mRNA vaccines in infectious disease prevention and cancer therapy.

We developed RNA Gene Writers that use all-RNA compositions and the process of target-primed reverse transcription to integrate large genetic payloads into the genome. By using T cell-targeted LNPs to deliver RNA Gene Writer components in vivo, we demonstrated successful generation of functional CAR-T cells in different animal models.

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.