Cambridge Healthtech Institute’s 9th Annual

Oligonucleotide Discovery & Delivery

Optimizing Design and Performance and Reviewing Advances in the Clinic

March 13-14, 2024



Cambridge Healthtech Institute’s Oligonucleotide Discovery & Delivery conference reveals the latest strategies at the forefront of discovery, chemistry, and delivery with in-depth sessions on new chemistries, novel delivery mechanisms, and the most important preclinical and clinical advances. Industry and academic experts deliver detailed case studies on antisense, RNA, GalNAc, aptamers, conjugates, and other new modalities paving the way for the next generation of targeted oligonucleotides.

Tuesday, March 12

Registration Open12:00 pm

Recommended Short Course*5:30 pm

SC1: Safety & Toxicity of Nucleic Acids

*Separate registration required. See short course page for details.

Wednesday, March 13

Registration and Morning Coffee7:00 am

Organizer's Welcome Remarks8:30 am

INNOVATIVE APPROACHES TO RNAi AND siRNA DEVELOPMENT AND DELIVERY

8:40 am

Chairperson's Opening Remarks

Ekkehard Leberer, PhD, Senior Life Sciences Consultant, ELBIOCON; Advisor, Neuway Pharma

8:45 am

Optimizing Oligonucleotides for Extrahepatic Targets through Stereopure Design

Chandra Vargeese, PhD, CTO & Head, Platform Discovery Sciences, Wave Life Sciences

Wave’s PRISM platform enables the generation of chimeric backbone-containing stereopure oligonucleotides with improved pharmacological properties through position-controlled chemistry and stereochemical configuration. Here, we will provide an update on our progress in developing oligonucleotides that are optimized for distinct high-priority genetic targets, modalities, and tissues. As illustration, we will describe our development of stereopure phosphoryl guanidine (PN) backbone-containing chimeric oligonucleotides for RNA interference (RNAi) applications in hepatic and extrahepatic tissues.  

9:15 am

Investigating Chemistry and Route of Administration for siRNA Delivery to the Skin

Julia Alterman, PhD, Assistant Professor, RNA Therapeutics Institute, University of Massachusetts Medical School

siRNAs have the potential to target many genetically defined disorders. In this study we investigate the impact of chemical architecture and route of administration on siRNA delivery to human skin ex vivo and pig skin in vivo. Our data outline an effective strategy for functional delivery of siRNAs enabling efficient silencing of genetic targets for dermal indications.

9:45 am

RNAi Conjugates for Cancer Immunotherapy

Shanthi Ganesh, PhD Director, Pharmacology, Global Nucleic Acid Therapies, Novo Nordisk

Most refractory malignant solid tumors create an immunosuppressive tumor microenvironment (TME), rendering them resistant to standard-of-care immune checkpoint inhibitors (CPIs). We investigated the feasibility of applying systemically delivered RNAi agent to silence the mRNA of a historically undruggable target, that involved in mediating immune suppression in TME, directly in tumor-associated immune cells. In preclinical rodent tumor models, GalXC-Plus conjugates selectively silenced the mRNA in multiple relevant cell types, reduced the protein levels, and increased cytotoxic T-cell infiltration. In immunotherapy resistant tumors, RNAi-mediated silencing resulted in tumor growth inhibition, which was further enhanced in combination with CPIs. A human active STAT3 conjugate is currently in Phase 1 clinical trial for treatment of immunotherapy refractory cancer types (NCT06098651).

10:15 am Multiomic Spatial Biodistribution Analysis Tools for Oligonucleotide-Based Therapeutics

Alpana Kumari, Manager, Business Development, Bio-Techne

Advanced Cell Diagnostic’s miRNAscope and RNAscope Plus assays provide spatial and cell-specific information about therapeutic biodistribution of siRNA, Antisense Oligo (ASO), and other short oligos within intact animal models and patient biopsies. We use proprietary oligo probes designed to target short non-coding RNAs and mRNAs in conventional FFPE, frozen tissues, or cultured cells. Unmodified or chemically modified short RNAs can be detected with high sensitivity. The assay can be easily combined with traditional protein detection methods for co-detection of oligos and protein. 

Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing10:45 am

11:35 am

GalAhead™ muRNA: A Proprietary GalNAc-RNAi Therapeutic Platform for simultaneous Downregulation of Multiple Genes.

Jim Weterings, PhD, Vice President Research, RNA Therapeutics & Delivery, Sirnaomics

We developed an unconventional GalNAc-based RNAi therapeutic technology, GalAhead, comprising two key components – mxRNA (miniaturized RNAi triggers) and muRNA (multi-unit RNAi triggers). mxRNAs are composed of single ~30nt oligonucleotides and downregulate individual genes, while muRNAs are comprised of 2 or more oligonucleotides and can simultaneously silence two or more targets. We will present data demonstrating validity of the GalAhead technology in vitro and in vivo, as well as progress report with quickly expanding and progressing GalAhead-based therapeutic pipeline, with first program entering clinical trials earlier this year.

12:05 pm

Improving the Safety and Specificity of RNAi Therapeutics

Maja Janas De Angelis, PhD, DABT, Senior Director, Investigative Toxicology, Alnylam Pharmaceuticals

Nonclinical safety screening of GalNAc-siRNAs is typically carried out in rats at exaggerated exposures in a repeat-dose regimen. We have previously shown that at these suprapharmacological doses, hepatotoxicity observed with a subset of GalNAc-siRNAs is driven by antisense strand seed-mediated off-target activity. To increase specificity, we developed a novel design strategy termed ESC+, which utilizes chemical modifications that thermally destabilize the base pairing between the seed region and off-target mRNAs.

Transition to Lunch12:35 pm

12:45 pm LUNCHEON PRESENTATION:Unlocking Success in Oligo-Based Therapeutics: Insights from WuXi TIDES

Yvonne Angell, Executive Director, Head of TIDES Discovery Project Management

In the rapidly evolving landscape of oligo-based therapeutics, WuXi TIDES stands as a beacon of innovation and efficiency. Our comprehensive platform is meticulously engineered to accelerate the trajectory from discovery to Commercialization, leveraging state-of-the-art tools and methodologies.

 

Join us for an engaging presentation as we illuminate the hurdles encountered during the discovery phase of oligo-based therapeutics. Through two compelling case studies, we will unravel our journey towards advancing a program from Discovery to Development. From overcoming technical challenges to refining strategic approaches, our experiences offer invaluable lessons for navigating the complexities of this vital field. This talk will allow you to gain firsthand insights into our successes and learnings, poised to inspire and inform your own endeavors in oligo-based therapeutics.

Session Break1:15 pm

ENHANCING DELIVERY WITH AOC TECHNOLOGY AND LIPID NANOPARTICLES

2:00 pm

Preclinical Considerations for Successful Antibody-Oligonucleotide Conjugate Development

Aaron Moss, PhD, Senior Director, Pharmacokinetics and Pharmacodynamics, Avidity Biosciences

Antibody-oligonucleotide conjugate (AOC) technology is a promising approach to facilitate the functional delivery of oligonucleotides to a variety of target tissues. We utilized targeting TfR1 to deliver therapeutic oligonucleotides to muscle tissue for the treatment of rare neuromuscular diseases. The preclinical systemic and tissue pharmacokinetics of AOCs in vivo will be discussed, including strategies to maximize receptor-mediated tissue uptake.

Q&A with Session Speakers2:30 pm

Refreshment Break in the Exhibit Hall with Poster Viewing3:00 pm

PLENARY KEYNOTE SESSION

3:40 pmOrganizer's Welcome Remarks
3:45 pm

Plenary Chairperson's Remarks

Jim Weterings, PhD, Vice President Research, RNA Therapeutics & Delivery, Sirnaomics

3:50 pm

Biomimetic Chemistry of RNA Therapeutics

Mano Manoharan, PhD, Distinguished Scientist & Senior Vice President, Innovation Chemistry, Alnylam Pharmaceuticals

Achieving success in RNA therapeutics depends on proper understanding of mechanisms of nature. In stages of discovery, delivery, and development of RNA-based therapeutics we follow and mimic many natural processes. We will illustrate this concept by taking several key steps of molecular mechanisms involved and examples of medicines which are either approved or in clinical development.

4:20 pm

Applications for mRNA Therapeutics: Immunological Issues and Considerations

Arthur Krieg, MD, Adjunct Professor, University of Massachusetts, Chan School of Medicine

From an immunological perspective, there are 3 distinct categories of mRNA therapeutics, including: 1. Protein expression mRNAs (including e.g., enzyme replacement, antibody expression, gene editing with encoded programmable nuclease), wherein any immune activation is highly undesirable; 2. Infectious disease mRNA vaccines such as COVID (immune activation desirable to induce neutralizing antibodies); and 3. Cancer mRNA vaccines (immune activation desirable to induce CD8+ T cells able to kill tumors). Achieving these distinct immune effects requires intentional design of the mRNA and delivery system, which will be reviewed.

Welcome Reception in the Exhibit Hall with Poster Viewing4:50 pm

Close of Day5:50 pm

Thursday, March 14

Registration and Morning Coffee8:00 am

PLENARY KEYNOTE SESSION

8:30 amOrganizer's Welcome Remarks
8:35 am

Plenary Chairperson's Remarks

Paloma Giangrande, PhD, CTO, Eleven Therapeutics

8:40 am

Realizing the Promise of in vivo CRISPR Therapeutics

Sean Burns, PhD, VP Disease Biology, Intellia Therapeutics Inc.

NTLA-2001 is an investigational CRISPR-based therapy being evaluated in a Phase 1, two-part, open-label study in adults with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) or with cardiomyopathy (ATTR-CM). NTLA-2002 is being developed for hereditary angioedema (HAE), designed to knock out the KLKB1 gene in the liver with the potential to permanently reduce total plasma kallikrein protein and activity, a key mediator of the disease. NTLA-2002 is being evaluated in a Phase 1/2 study in adults with Type I or Type II HAE. Preclinical and clinical data for both programs will be presented.  

9:10 am

Harnessing RNA Metabolism for Precision RNA Therapeutics

Jeffery M. Coller, PhD, Bloomberg Distinguished Professor of RNA Biology and Therapeutics, Johns Hopkins University

We have created a therapeutic technique that enhances mRNA translation. This technology has numerous clinical applications and works by binding to mRNA and improving translation. The approach offers key benefits: it is disease-modifying, restoring normal protein levels; it is mutation agnostic; it can be tailored to precisely control expression, reducing the risk of overexpression; and lastly, it is applicable across indications and highly versatile.

Coffee Break in the Exhibit Hall with Poster Viewing9:40 am

OPTIMIZING DESIGN, DELIVERY, AND PERFORMANCE

10:30 am

Chairperson's Remarks

Chandra Vargeese, PhD, CTO & Head, Platform Discovery Sciences, Wave Life Sciences

10:35 am

KEYNOTE PRESENTATION: Biological Activity of Thiomorpholino Oligonucleotides

Marvin Caruthers, PhD, Distinguished Professor, University of Colorado

Collaborations with over 20 laboratories elsewhere have shown that thiomorpholino oligonucleotides are more active biologically than any of the standard ASOs including 2'-MOE and 2'-OMe oligomers. In several preliminary studies in mice and zebra fish, the thiomorpholino oligonucleotides have been shown to be far less toxic than any other tested analogue. These various studies include research focused on rare genetic diseases, cancer, type II diabetes, and various neurological diseases.

11:05 am

Harnessing Nucleic Acid Immunity for Cancer Immunotherapy with Immune-Stimulatory Oligonucleotides

Arthur Krieg, MD, Adjunct Professor, University of Massachusetts, Chan School of Medicine

Vertebrate immune systems have evolved nucleic acid immune sensing receptors to detect the presence of foreign nucleic acids, and to activate innate and adaptive immune defenses. Synthetic RNA and DNA ligands for these receptors induce antibody and T cell responses that underly the efficacy of mRNA vaccines and may be used for in situ immunization to treat cancer. Understanding the different biology of these receptors, including TLR3, TLR7, TLR8, TLR9, cGAS/STING, and the RIG-I-like receptors is essential for optimizing cancer immunotherapy in humans.

11:35 amEnjoy Lunch on Your Own
1:00 pm

Development of Gemcitabine-Modified miRNA Mimics as Novel Anti-Cancer Therapy for Pancreatic Ductal Adenocarcinoma

Jingfang Ju, PhD, Professor, Renaissance School of Medicine, Stony Brook University; Co-Founder, Curamir Therapeutics, Inc.

We developed a new treatment strategy by modifying tumor suppressor miRNAs, hsa-miRNA-15a (miR-15a) with gemcitabine (Gem), to create Gem-modified mimics of miR-15a (Gem-miR-15a). Gem-miR-15a is a potent inhibitor to eliminate patient-derived pancreatic cancer organoids and mouse tumor models without delivery vehicle.

1:30 pm

The Endosomal Escape Vehicle Platform Enhances the Delivery of Oligonucleotides to Skeletal and Cardiac Muscle

Leo Ziqing Qian, PhD, Co-Founder & Vice President, Discovery Research, Entrada Therapeutics

To overcome current limitations of oligonucleotide therapeutic delivery, we have designed a family of proprietary cyclic CPPs that form the core of our Endosomal Escape Vehicle (EEV) technology and covalently conjugated it to oligonucleotides. Using preclinical models of Duchenne muscular dystrophy (DMD), we demonstrated the ability of our EEV platform technology to efficiently deliver oligonucleotides to skeletal and cardiac muscle, the primary sites of pathology in DMD.

2:00 pm

Long-Acting Nucleic Acid Formulations With Silica Matrix

Milla Runsala, PhD, Business Development Manager, DelSiTech Ltd

DelSiTech technology offers a way to deliver APIs over an extended period by encapsulating them in biodegradable silica. Our recent findings on injectable, long-acting antisense oligonucleotides demonstrate the capability of the technology to support the generation of durable treatments, from sensitive and often highly complex molecules. Join us as we explore our technology and how it can support the progression of long-lasting nucleic acid–based therapies such as oligonucleotide, mRNA, and more.

INTERACTIVE BREAKOUT DISCUSSIONS

2:30 pmInteractive Breakout Discussions

Interactive Breakout Discussions are informal, moderated, small-group discussions, allowing participants to exchange ideas and experiences and develop future collaborations around a focused topic. Each discussion will be led by a facilitator(s) who keeps the discussion on track and the group engaged.  To get the most out of this format, please come prepared to share examples from your work, be a part of a collective, problem-solving session, and participate in active idea sharing. Please visit the Breakout Discussion page for a complete listing of topics and descriptions.

IN-PERSON ONLY BREAKOUT DISCUSSION:

Successful Oligonucleotides for Extrahepatic Tissues and Strategic Collaboration between Academia and Industry

Ken Yamada, PhD, Assistant Professor, RNA Therapeutics Institute, University of Massachusetts Medical School

  • What are the current chemistry demands and promising strategies towards successful therapeutic oligonucleotides for extrahepatic tissues?
  • -Oligonucleotide backbone modification
    -Delivery strategies
    -Strategies to modulate cell-type specificity
    -Strategies to facilitate endosomal escape
  • How can we further amplify the benefits of collaboration between academic labs and biotechs?
    -Ideal research partnerships between academic labs and biotechs that synergistically facilitate oligonucleotide drug development
    -Future path for n=1 therapeutics
IN-PERSON ONLY BREAKOUT DISCUSSION:

From Early Discovery and the Clinic to Collaborations Between Big Pharma and Small Biotechs

Marvin Caruthers, PhD, Distinguished Professor, University of Colorado

Developments from Early Discovery Through to Late-Stage Clinical Programs

  • How do you know your discovery should move toward the clinic
  • Patents
  • Steps toward the clinic-biology/biochemistry/chemistry, cell biology, animal studies, toxicology, and who/how to carry out a clinical trial

Strategic Collaboration Between Big Pharma and Small Biotechs

  • How do you define a strategic collaboration-from the perspective of big pharma and small biotech (i.e. why a collaboration)
  • Conditions for a strategic/successful collaboration
  • Oligonucleotide CMC and Regulatory Strategies​

Refreshment Break in the Exhibit Hall with Last Chance for Poster Viewing3:10 pm

NOVEL ADVANCES WITH ANTISENSE OLIGONUCLEOTIDES (ASOs)

3:45 pm

Treatment of Cancer with Antisense Oligonucleotides Targeting the Immunosuppressive Tumor Microenvironment

Frank Jaschinski, PhD, CSO, Secarna Pharmaceuticals

The immunosuppressive tumor microenvironment is an efficient barrier that protects the tumor from destruction by the immune system. It comprises several targets that are predestined as targets for therapeutic antisense oligonucleotides (ASOs). As an example, we will present data showing that ASOs suppressing expression of the multifactorial protein NRP1 are a promising option for treatment of cancer.

4:15 pm

Production of Maleimide-Conjugated ASO for Subsequent Functionalization: Lessons Learned during Development

Zifan Li, PhD, Senior Scientist, Analytical Development, Biogen

Functionalization of therapeutic oligonucleotides by conjugating to multiple modalities may be beneficial for their efficacy or delivery. Certain examples like GalNAc have been widely applied in therapeutic ASO and siRNA development. Maleimide-conjugated ASO can be easily functionalized by conjugating to thiol-bearing modalities. During the manufacturing development of such conjugates we have encountered several difficulties, conquered them, and learned lessons. This presentation intends to share what we learned.

4:45 pm

Toehold Nanoarchitecture That Mitigates ASO off-Target Interactions

Tsuyoshi Yamamoto, PhD, Associate Professor, Director, Liid Pharma, Nagasaki University

This presentation introduces a novel nanoarchitecture, BROTHERS or BRO, designed to mitigate off-target interactions of antisense oligonucleotides (ASOs). The BRO, comprising a typical gapmer ASO and a complementary peptide nucleic acid (PNA) strand, deters non-specific protein and RNA binding. Harnessing its inherent free energy, BRO triggers a toehold-mediated strand displacement reaction, which enhances ASO's mismatch recognition, minimizing hybridization to RNA off-targets. Consequently, BRO enhances therapeutic window of ASOs.

Close of Conference5:15 pm






Call For Papers