Souffle Therapeutics is focused on translating a novel platform for discovery of new cell- and tissue-specific ligands into a broad pipeline of targeted genetic medicines. Souffle has demonstrated stronger, safer, and more durable delivery to myocytes of the heart and muscle, while avoiding concomitant silencing in other tissues screened, even at supratherapeutic doses. Souffle is pursuing several programs in genetically defined as well as broader indications enabled by this platform.

SanegeneBio is developing next-generation RNAi medicines powered by improvements in oligonucleotide and delivery chemistries, including our differentiated LEAD extrahepatic delivery technology and bispecific siRNA platform. This presentation will update preclinical and clinical progress across our autoimmune and cardiometabolic portfolio, including for our most advanced program targeting C3 for autoimmune nephropathies. We will also cover first-in-class targets and new approaches for systemic subcutaneous delivery to relevant cell types.

Oligonucleotide conjugates can transform tissue targeting and therapeutic index, yet delivery itself may become a principal source of toxicity. This presentation will examine how receptor-mediated uptake, tissue accumulation, intracellular trafficking, linker chemistry, and conjugate architecture influence organ-specific injury, immune activation, and species translation. Using representative clinical and preclinical examples, the presentation will highlight translational safety principles for dose selection, biomarker monitoring, and rational conjugate design to separate pharmacologic benefit from delivery-driven toxicity during successful clinical development.

SpiNA, a stereopure siRNA design, supports potent, durable knockdown in mice. We explored whether metabolic phenotypes could be improved in a mouse model of diet-induced obesity by reducing Activin E (Act E) expression that regulates adipocyte lipolysis. INHBE-3 is an N-acetylgalactosamine (GalNAc)-conjugated SpiNA targeting Inhbe, which encodes Act E. A single dose of INHBE-3 reduced Act E protein (75%) and body weight, improved body composition, and reduced adipose tissue inflammation.

The selection of AOC components—antibody, linker, and siRNA—can be a daunting task. Biophysical characterization of each conjugate can guide the selection of the optimal combination of the 3 components for the ideal therapeutics.

This talk evaluates Ab-SENS (Antibody-conjugated Selectivity Enabling Nanoshell), a delivery platform for breast cancer treatment. Although siRNA is a clinically validated platform, its potential depends on effective delivery and targeting. Ab–SENS is designed to overcome the low loading efficiency of direct antibody–siRNA conjugates by taking advantage of its high loading capacity. HER2 Ab–SENS reduced systemic toxicity, and PLK1 silencing induced potent antitumor activity when compared to direct PLK1 siRNA conjugates.

Gensaic is a multifunctional RNA therapeutic company focused on cardiometabolic disease and aging. Its discovery engine, FORGE is a generative-AI engine built on two pillars: 1) in-vivo unbiased protein evolution of extrahepatic ligands and 2) a dual-gene perturbation model trained on in-vivo disease models. Gensaic's lead product, G001, is a best-in-class dual-siRNA-peptide conjugate showing >35% weight-loss in DIO mice while gaining up to 5% lean mass, all while increasing insulin sensitivity and dramatically improving lipid and cholesterol panels. G001 is expected to dose patients in Q1 2028. Gensaic has an in-vivo pipeline spanning 15 gene-combinations across various PD models.

Oligonucleotide delivery beyond the liver remains a central challenge in nucleic acid therapeutics. This presentation will compare RNA nanostructures, micelles, exosomes and other targeted delivery approaches across key parameters including tissue specificity, payload capacity, intracellular delivery, pharmacokinetics and manufacturability. Hepatic and extra-hepatic applications will illustrate how delivery architecture can be matched to therapeutic objectives, including emerging opportunities for targeted combination and multi-payload therapeutics.

Efficient, targeted delivery to extrahepatic tissues remains a major focus of the oligonucleotide therapeutics field. Here, we describe transferrin receptor 1 (TfR1)-targeting aptamer-siRNA conjugates that enable selective delivery to skeletal muscle and sustained myostatin silencing for up to three months following a single systemic administration in mice. We explore how chemistry and architecture influence tissue accumulation, pharmacokinetics, and silencing, establishing a promising platform for RNA therapeutics targeting skeletal muscle.