Modulation of pre-mRNA splicing using antisense oligonucleotides (ASOs) is a clinically validated therapeutic strategy, with multiple FDA-approved drugs. Current splice-switching ASOs (SSOs), primarily based on phosphorodiamidate morpholino oligomer (PMO) and 2'-O-methoxyethyl phosphorothioate (2'-MOE PS) chemistries, have certain limitations. Our laboratory focuses on developing innovative SSO designs and chemistries to overcome these challenges and enhance therapeutic efficacy. Here, we present our recent advances in developing next-generation SSOs for therapeutic applications.

The presentation will describe the use of a virus-like particle to deliver therapeutic RNAs to the brain for the treatment of CNS diseases. This is making use of the brain tropism of a capsid protein derived from the John Cunningham virus. The therapeutic potential of this drug-delivery system will be illustrated by mRNA-based enzyme replacement to repair the genetic defect in metachromatic leukodystrophy, a monogenetic CNS lysosomal-storage disorder.

SECN-15 is a high-affinity-modified antisense oligonucleotide (ASO) targeting NRP1, a tumor-promoting factor expressed by multiple cell types within the tumor microenvironment. In preclinical models, systemic administration of SECN-15 achieved sustained tumor exposure, resulting in potent target knockdown in relevant cell populations and durable suppression of soluble NRP1 in plasma. Moreover, SECN-15 demonstrated robust antitumor activity both as a monotherapy and in combination with anti-PD-1 therapy, supporting further clinical development.

Wave’s PRISM platform enables the generation of chimeric phosphoryl guanidine (PN) backbone-containing stereopure oligonucleotides with position-controlled chemistry and stereochemical configuration. Examples provided will include where stereopure design and incorporation of PN linkages improve the pharmacological properties of oligonucleotides designed for distinct genetic targets, modalities, and tissues. Ongoing clinical-trial data suggest that the improved pharmacological properties of investigational PN-containing oligonucleotides are translating into the clinic.

The identification of miR-22 as a regulator of lipid and energy homeostasis opened a new therapeutic avenue for obesity. These insights led to RES-010, an antisense oligonucleotide designed to inhibit miR-22 and promote metabolic remodeling. Studies in mice, non-human primates, and human adipose organoids provided preclinical evidence supporting improved body composition and potential complementarity with GLP-1 receptor agonists. These findings supported progression into clinical development, with a completed first-in-human Phase 1 study and an ongoing Phase 1b study assessing safety, target engagement, and biomarkers of metabolic response, supporting further exploration of miR-22 inhibition in obesity and related metabolic disorders.

Wave’s PRISM platform enables the generation of chimeric backbone-containing oligonucleotides with position-controlled chemistry and stereochemical configuration, allowing us to use a rational approach to oligonucleotide design, optimizing to distinct tissues, target sequences, and endogenous enzyme engagement. Here, we will describe our progress in improving the pharmacological properties of small interfering RNA (siRNA). We achieve potent, durable knockdown in liver and kidney in mice with our stereopure siRNA design called SpiNA.

EnPlusOne’s enzymatic, aqueous RNA synthesis platform has enabled the site-specific incorporation of modifications that are difficult with the traditional chemical synthesis approach. Here, we present the incorporation of different internucleotide phosphonates and discuss their effects on nuclease stability, knockdown, and off-target effects.

Nav1.7, encoded by SCN9A, is genetically validated as a key regulator of human pain but has proven challenging to drug selectively. We developed QVP-2421, an intrathecally delivered antisense oligonucleotide designed for selective and durable reduction of Nav1.7 expression. QVP-2421 was identified through an integrated discovery platform combining machine-learning-guided sequence prioritization with high-throughput all-optical electrophysiology in sensory neurons. Functional screening enabled selection beyond target knockdown alone, and QVP-2421 rescued hyperexcitability in patient-derived iPSC sensory neurons carrying a gain-of-function SCN9A variant. In a repeated-dose non-human primate study, QVP-2421 achieved robust Nav1.7 knockdown in lumbar dorsal root ganglia and spinal cord, with a favorable tolerability profile and no observed hypotension. These results demonstrate how computational design and functional neuronal phenotyping can support development of a genetically validated but challenging pain target.