Main Conference Day 3木曜日, 26 2月 2026

We developed a clinically inspired targeted LNP system for CD8⁺ T cell–directed mRNA delivery. By precisely tuning per-particle ligand density, we achieved efficient CAR mRNA transfection and robust in vivo CAR-T generation, leading to functional B cell depletion at double-digit µg/kg doses. This scalable, non-viral approach represents a promising platform for off-the-shelf immunotherapy, enabling targeted and dose-efficient programming of immune effector cells.

The FORCE platform leverages TfR1 biology to enable delivery of oligonucleotide or biologics to muscle and CNS, with potential applicability to a wide range of neuromuscular diseases. FORCE demonstrated high therapeutic potential in preclinical models of myotonic dystrophy type 1 (DM1) and non-human primates. With DYNE-101, the platform achieved clinical proof-of-concept in DM1 patients, with correction of the underlying splicing defect, broad functional improvement, and a favorable safety profile to date.

The FDA Prescription Drug User Fee Act (PDUFA) Act VII Commitment Letter required FDA to implement a Chemistry, Manufacturing, and Controls (CMC) Development and Readiness Pilot (CDRP) where products regulated by the Center for Biologics Evaluation and Research (CBER) as well as the Center for Drug Evaluation and Research (CDER) may receive expedited and accelerated development. This aims to provide patients with earlier access to anticipated clinical benefit. Patient access to treatments with accelerated designations should not be delayed by CMC challenges. The presentation will explore challenges to expedited CMC development and strategies for improvement.

Oligonucleotides are now clinically validated medicines, but their use and efficacy in kidney has been restricted. We are targeting the proximal tubule cells using conjugated siRNA that have a ligand for the endocytic receptor megalin.

siRNA delivery platforms capable of accessing both central and peripheral tissues are critically needed to expand the therapeutic potential of oligonucleotides. Here, we target IGF1R receptor for siRNA delivery across both central and peripheral tissues, offering a complementary strategy for expanding the therapeutic landscape of oligonucleotide delivery.

To date, no approved siRNA drugs are capable of selectively silencing mutated genes without affecting wild-type alleles. To overcome this limitation, we have developed next-generation SNPD-siRNAs (Single-Nucleotide Polymorphism Distinguishable siRNAs) that achieve allele-specific silencing at single-nucleotide resolution. By precisely distinguishing mutated alleles from normal, these siRNAs offer a powerful therapeutic strategy for hereditary disorders and cancer-associated mutations, representing a major advance toward truly personalized nucleic acid therapeutics with unprecedented precision.

This presentation will highlight recent progress in the discovery and development of Antibody Oligonucleotide Conjugates. Insights into muscle and cardiac tissue delivery, platform optimization and the preclinical translational of the AOC platform across rare neuromuscular diseases will be discussed.

Antibody–oligonucleotide conjugates (AOCs) are an emerging class of therapeutics that combine the cell-targeting specificity of antibodies with the gene-silencing capability of oligonucleotides. While highly promising, the hybrid nature of AOCs presents unique analytical challenges in characterization, metabolite profiling, and bioanalysis. In this study, we present an integrated liquid chromatography–high-resolution mass spectrometry (LC-HRMS) workflow designed to support AOC development from early discovery through in vivo evaluation. We utilize LC-HRMS to rapidly confirm oligonucleotide sequence, molecular integrity, and drug-to-antibody ratio, enabling efficient batch release and structural verification. For metabolite profiling, ion-pairing reversed-phase LC-MS (IPRP-LC-MS) is employed to identify and semi-quantitatively assess oligonucleotide metabolites in tissue samples, providing insights into tissue-specific distribution and lysosomal degradation. Additionally, leveraging a Proteinase K digestion sample preparation approach, we demonstrate the application of IPRP-LC-MS for the quantitative analysis of intact AOCs in plasma, supporting sensitive and selective pharmacokinetic assessments. Together, these LC-HRMS–based assays form a robust and scalable platform that addresses the analytical needs of AOC programs across CMC, nonclinical, and bioanalytical functions. This work highlights key strategies to accelerate AOC development and ensure regulatory readiness.

VP-001 is a peptide phosphorodiamidate Morpholino oligomer (PMO) conjugate in clinical development for the treatment of retinitis pigmentosa RP-11. Due to the chemical complexity of the compound, a highly basic naturally derived peptide conjugated to a neutral PMO of 25 bases and a size of > 10 kDa, analytical method development has been challenging. UV methodologies can provide good resolution but are not mass spectrometry (MS) compatible, while MS compatible methods suffer from poor resolution. The analytical method development journey has covered many techniques including ion-exchange, reverse-phase and hydrophilic interaction chromatography in conjugation with multiple ion-pair reagents and mixed mode column chemistries. This presentation covers the analytical method development from early-stage research grade material to clinical grade compound.

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.

TNBC accounts for about 10-15% of all breast cancers and differs from other types of invasive breast cancer in that they grow and spread faster, have limited treatment options, and a worse prognosis. Therefore, TNBC has a very low survival rate when it metastasizes to the lungs after surgery. We have recently developed a novel Aptamer-Drug Conjugate(ApDC) implantable anticancer agent that shows remarkable survival rate by preventing recurrence and metastasis after surgery in TNBC orthotopic mouse model. This ApDC device is thought to be a new surgical strategy to prevent metastasis in treating TNBC. In this study, we conjugated various types of drugs to aptamers and carried-out its preparation, structural analysis, in-vivo drug release, and chemistry, manufacturing, and control (CMC) of the resulting ApDC. The CMC of the novel ApDC involve precise synthesis and purification to ensure batch consistency, therapeutic efficacy and patient safety. Structural analysis of ApDC by NMR, CD, and UV spectroscopy revealed that it predominantly forms a highly stable and unique secondary structure. These findings provide important structural insight for its biological function and application as potential treatment for TNBC. We will present valuable insights into the development and characterization of aptamer-based drug delivery systems, highlighting their potential for cancer targeted therapy applications.