We have applied phosphoryl guanidine backbone chemistry (PN chemistry) to oligonucleotides. Similar to the phosphorothioate (PS) backbone, PN is a chiral modification, so we apply it as part of our stereopure platform. The application of PN chemistry has improved the pharmacological properties of our stereopure molecules in preclinical studies across oligonucleotide modalities. Early data from our ongoing clinical trials suggests these improved pharmacological properties are translating into the clinic.

The FORCE platform is a novel technology that harnesses the natural expression of TfR1 on muscle cells for targeted delivery of rationally designed therapeutics with the goal of addressing the underlying cause of rare genetic muscle diseases. Data from Duchenne muscular dystrophy (DMD) and myotonic dystrophy type 1 (DM1) preclinical models demonstrate that administration of DYNE-251 and DYNE-101, respectively, results in delivery of oligonucleotides directly to cardiac and skeletal muscle. DYNE-251 and DYNE-101 are expected to begin patient dosing in Phase I/II clinical trials in mid-2022.

We have developed AIMers, A-to-I RNA base editing oligonucleotides that engage endogenous ADAR enzymes to edit RNA sequences with high efficiency and specificity. Our first RNA editing program was launched to correct a disease-causing, protein-coding mutation in SERPINA1 mRNA. RNA editing is a versatile technology, with enormous opportunity to address diseases with unmet need. We will provide an update on our preclinical efforts to expand the target space for this new technology, including modulating protein-protein interactions and upregulating gene expression.

RNAi therapeutics has potential to target a variety of disease indications by targeting hepatic as well as extra-hepatic target genes. To achieve this goal, the development of optimal delivery methods for each target organ is essential. We have successfully established lipid-conjugated asymmetric siRNA (asiRNA) targeting skin and ocular tissues, to develop therapeutic programs against hypertrophic scar, androgenic alopecia, and age-related macular degeneration. We also established GalNAcTang, our own GalNAc-based liver targeting strategy to tackle diseases such as HBV and NASH. Preclinical and clinical updates on each program will be presented.

RIGImmune is developing a new class of RNA oligonucleotides that activate the innate immune sensor RIG-I. The lead compound is being developed as a pan-viral agent and for immuno-oncology.

• What are emerging innovative technologies in oligo R&D, focusing on in particular:
  - AI/machine learning
  - Delivery strategies
  - Safety screening
• Challenges in the adoption and implementation of innovative technologies
• Strategies to keep up with the rapidly evolving field
• What’s next in oligo discovery and delivery innovation?

rnatics has developed first-in-class, macrophage-specific delivery technology for targeted RNA therapeutics. Cell surface receptors naturally present in high density on macrophages enable the targeted delivery to tissue resident macrophages through tailored carbohydrate ligands. The achievement of specific and efficient delivery to macrophages is a breakthrough technology that enables access to multiple tissues previously not accessible to RNA therapeutics. The most advanced drug candidate, RCS-21, is in development for the treatment of severe cases of COVID-19. RCS-21 is delivered by inhalation and addresses the macrophage-mediated lung damage following a SARS-CoV-2 infection. We aim to start clinical trials in 2023.

We have developed a novel oligonucleotide delivery platform by conjugation with Entrada’s proprietary Endosomal Escape Vehicle (EEV) technology, a class of cyclic peptides designed to facilitate intracellular delivery and endosomal escape. Preclinical studies in several disease models have confirmed the significant therapeutic potential of this approach and demonstrated that the EEV platform can serve as a general and highly efficient delivery technology for the targeted delivery of therapeutic oligonucleotides.

e-therapeutics (“ETX”) combines data, computation and biology to discover and develop RNAi medicines at speed. The company generates mechanistic network biology models, then analyzes these networks to interrogate disease process complexity, test therapeutic hypotheses, identify novel drug targets, and then design nucleotide sequences. ETX has built a comprehensive knowledgebase of proprietary and public hepatocyte-relevant data that it mines using deep learning and then employs proprietary GalNAc-siRNA technology to target hepatocytes in the liver.