Main Conference - Day 2 (May 13)Wednesday, 13 May 2026

Oligonucleotide therapeutics (ONTs) are poised to become the third pillar of modern medicine. However, the practical and large-scale synthesis of ONTs and their constituent nucleoside analogue (NA) building blocks remains a major challenge. As each of the NA units must be individually designed and tailored to enhance the desired ADMET properties of the ONT, identifying economic, flexible, and scalable syntheses of these compounds is of critical importance. To date, the field has relied almost exclusively on carbohydrates as starting materials for NA synthesis. While these compounds are enantiopure and share common structural and stereochemical features with NAs, their conversion into NAs often requires long, challenging, low-yielding and expensive synthetic campaigns. As a result, a large fraction of ONT chemical space remains unexplored and the full impact of chemical modification on the pharmacokinetic properties of ONTs remains poorly understood. Here, we present a streamlined platform to produce NAs that should improve access to precision edited ONTs. This approach uses achiral starting materials and relies on a dual organocatalyst, one-pot process to furnish a key class of ONT building blocks: the RAvIN ketones (RKs). Notably, RKs can incorporate appropriately protected natural nucleobases as well as nucleobase analogues, be made on scale in 2-4 steps with carbohydrate-like levels of enantiomeric purity and are readily diversified to create the next generation NAs required to improve physiochemical properties of ONTs. Finally, we demonstrate the versatility and potential of this methodology in a total synthesis of the all-MOE-modified RNA 18mer nursinersen.

Enzymatic methods are transforming oligonucleotide synthesis by offering higher precision, milder conditions, and greater sustainability compared to traditional chemical approaches. A key step in this process is the efficient production of 5′-NTP building blocks, where enzymatic routes provide clear advantages over chemical synthesis, such as better selectivity, higher yields, and simpler workflows. Here we showcase powerful enzymatic strategies for efficient 5′-NTP synthesis, leveraging purified enzymes with nucleobases or nucleosides as starting materials. These approaches unlock new possibilities through integrated ATP regeneration systems that drive efficiency and sustainability. By highlighting the transformative potential of in vitro enzymatic cascade reactions, we emphasize their value as cutting-edge tools with broad impact across basic research and industrial applications.

The rapidly growing number of therapies approved and in advanced clinical trials is placing unprecedented demands on our capacity to manufacture oligonucleotides at scale. This talk will describe several complementary biocatalytic approaches to efficiently produce oligonucleotides in a more sustainable fashion.

Traditional solid-phase oligonucleotide manufacturing faces inherent limitations that may restrict the broader application of synthetic oligonucleotide therapeutics, particularly in prevalent disease areas. To address these challenges, we have been developing a next-generation, hybrid manufacturing platform that integrates solid-phase synthesis of short blockmers and solution-phase, enzyme-mediated ligation reaction. This hybrid approach offers a promising path toward scalable, efficient, sustainable and high-quality production of therapeutic oligonucleotides. Alnylam’s progress in this approach will be presented.

The chemistry of oligonucleotide is getting increasingly complex with additions of modification that aim to improve their overall efficacy or biodistribution. The Mesylphosphoramidate is a chemical modification that requires the use of mesylazide, a potentially explosive reagent. This presentation describes how mesylazide was introduced at Biogen and its various risks mitigated.

As oligonucleotide therapeutics expand beyond rare diseases to treat prevalent conditions in larger patient populations, demand is surging dramatically. Traditional production faces process efficiency, environmental and scalability challenges that threaten accessibility. Exactmer is developing innovative solutions based on membrane separations to address these issues, including Nanostar Sieving, a fully liquid-phase synthesis platform. This presentation will report progress on how these innovations might enable more efficient large-scale manufacturing.

Standard and convergent methods of oligonucleotide manufacture largely depend on solid-phase oligonucleotide synthesis methodologies, reagents and materials that have remained relatively static as the technology has been scaled out. This presentation will discuss solid support and synthesis strategy advances to dramatically increase throughput of short therapeutic oligonucleotides and their fragments. As a result, synthesis solvents and manufacturing resource burdens are reduced.

The growing demand for therapeutic oligonucleotides requires new, efficient, scalable, and sustainable manufacturing solutions. This presentation will showcase Codexis’ ECO Synthesis® Manufacturing Platform, an enzymatic process for producing high-quality siRNA that operates under fully aqueous conditions, eliminating the need for highly reactive chemicals and dramatically decreasing acetonitrile use.

EnPlusOne’s enzymatic RNA synthesis is overcoming the limitations of traditional chemical methods. Our mild platform relies on water, a universal enzyme, and unprotected 3’-blocked nucleotides. We report updates to the format and composition of our solid support, which improved cycle yields and increased our scale. Enzyme side reactions were reduced, further helping cycle yields and reducing cycle time. Finally, we discuss additional approaches for improved synthesis efficiencies and downstream purification.