Day 1- Wednesday September 10thWednesday, 10 September 2025 - EST (Eastern Time, UTC-05:00

• Targeting microRNAs vs. siRNA/ASO: MicroRNAs regulate multiple genes simultaneously, offering comprehensive pathway control but with potential off-target effects. In contrast, siRNA/ASO technologies provide highly specific single-target precision with established delivery platforms and clinical validation.

• Nobel Prize Recognition: The groundbreaking discovery of microRNAs and their regulatory functions was honored with the Nobel Prize in Physiology or Medicine. This prestigious recognition underscores the significance of microRNA research in advancing both basic science and clinical applications.

• Investment Landscape: The microRNA therapeutics sector has experienced significant growth through mergers, acquisitions, and strategic investments from major pharmaceutical companies. Venture capital funding has accelerated the development of novel microRNA-based approaches for previously untreatable conditions across oncology, cardiovascular disease, and rare genetic disorders.

• Explore cutting-edge advancements in oligonucleotide synthesis, manufacturing, and delivery technologies

• Discuss strategies for overcoming key challenges in scaling oligo-based therapeutics from research to commercial production

• Examine innovative approaches to improve the efficacy, safety, and accessibility of siRNAs and antisense oligonucleotides

• The chemistry of oligonucleotides has played a crucial role in giving drug-like properties to oligonucleotides.
• To optimize oligonucleotide-based therapeutics, we explored oligonucleotide shapes that bring the 3'- and 5'-ends into transient cyclic structures.
• Oligonucleotide spatial structures exhibit reduced protein binding because of their shape and diminished interactions with pattern recognition receptors resulting from the inaccessibility of the 5’-end.
• These designs find extensive applications across diverse mechanisms of action for RNA therapeutics, including RNaseH-mediated knockdown, modulation of splicing, siRNA, and gRNA.

The transition from discovery to clinical manufacturing of oligonucleotide therapeutics can be hindered by fragmented workflows, supply chain vulnerabilities, and inefficient analytical method transfer. These issues can delay the progression of promising candidates. Through the selected case studies, we will explore how an integrated development framework can address these challenges with featuring harmonized process development, scalable oligonucleotide synthesis, and robust analytical method transfer. This approach would reduce the risk of raw material shortages and streamline analytical method transfer, and enables accelerated, reproducible, and high-quality advancement of oligonucleotide therapeutics toward clinical application.

The n-Lorem Foundation is pioneering a new paradigm in the development of individualized medicines for patients with ultra-rare genetic diseases. As a unique non-profit biotech, n-Lorem provides free, lifetime treatment to patients who would otherwise be invisible to traditional drug development pathways- those with mutations found in one or a few individuals worldwide.

In this talk, I will share how we are building a scalable and sustainable model that challenges the conventions of therapeutic development. Since our inception, we have received over 330 applications, launched more than 160 patient-directed drug discovery programs, submitted 25+ INDs, and treating 27 patients today. Our approach is deeply rooted in our over 35-year of experience in RNA-targeted therapies, especially antisense oligonucleotides (ASOs), offering precision tools that match the urgency and specificity of each patient’s condition.

I will provide an overview of our mission and model, outline our end-to-end discovery and development process, and discuss the scientific considerations that shape our work. Most importantly, I will highlight how our close working relationship with the FDA, our unwavering focus on individual patients, and our deep scientific and clinical expertise are allowing us to deliver highly personalized RNA-targeted treatments where no other options exist.

• Divalent siRNA (di-siRNA), a novel small interfering RNA technology, has potency, CNS distribution, and durability appropriate for neurological disease

• ATL-201, a di-siRNA targeting the KCNT1 sodium-activated potassium ion channel, gives selective knockdown of KCNT1 transcript and protein and reaches most neurons in the cortex following a dose into cerebrospinal fluid

• ATL-201 gives dose-dependent reduction in seizures lasting over four months in mice with Kcnt1-driven epilepsy and shows promise for treatment of gain-of-function KCNT1 genetic epilepsy

Cardiovascular disease is the leading cause of death worldwide; heart failure carries high mortality, and substantial health-economic burden. Cardiac infarcts can lead to loss of heart function and heart failure. Cardiomyocytes have limited regenerative capacity and current therapies only improve residual function and are not curative.

Small non-coding microRNAs delivered as synthetic mimics in cardiomyocyte specific lipid nanoparticles can reactivate cardiomyocyte proliferation in the adult heart. Preclinical studies in mice and pigs demonstrate increased cardiomyocyte division, reduced infarct size, and improved function after myocardial infarction.

The miRNA–LNP approach provides potent, transient, and repeatable effects with efficient myocardial delivery; Compared with AAV, protein and cell therapies, miRNA–LNPs offer better control of dose and optimal duration.

miRNA-based regenerative therapy represents a promising, scalable strategy for curative treatment against heart failure, warranting further clinical development and safety evaluation.

Delivery of RNAi to the central nervous system (CNS) has potential to treat a broad range of neurological disorders, but so far has been limited to intrathecal administration. Arrowhead Pharmaceuticals has developed an optimized CNS TRiM™ SC (Targeted RNAi Molecule, subcutaneous) platform which shows effective and long-lasting target inhibition throughout the CNS in preclinical species after systemic delivery. This platform can deliver siRNA to deep brain regions that weren’t feasible with intrathecal delivery, and the convenient administration route will enable application to larger patient populations such as Alzheimer’s and Parkinson’s disease. Preclinical data from several CNS TRiM™ SC programs that are currently moving into clinical development will be presented, including ARO-MAPT-SC, targeting Tau for the treatment of Alzheimer’s disease