Cambridge Healthtech Institute’s 5th Annual

Oligonucleotide Discovery and Delivery

Optimizing Design, Delivery and Performance

March 17-18, 2020


CHI’s Oligonucleotide Discovery and 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. Leading oligonucleotide scientists deliver detailed case studies on antisense, RNA, aptamers and conjugates – helping you develop the next generation of targeted oligonucleotide therapeutics.

Final Agenda

MONDAY, MARCH 16

12:30 - 6:30 pm Short Course and Pre-Conference Registration*

3:00 - 6:00 SC1: Circular RNAs as a New Therapeutic Modality

Instructors:

Samie Jaffrey, MD, PhD, Department of Pharmacology, Weill Medical College, Cornell University

Bojan Losic, PhD, Associate Professor, Department of Genetics and Genomic Sciences, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai

Additional Instructors to be Announced

6:30 - 9:30 SC2: Examining the Safety and Toxicity of Nucleic Acid Therapeutics

Instructors to be Announced

*Separate registration required

TUESDAY, MARCH 17

7:00 am Registration and Morning Coffee

OPENING PLENARY

8:00 Welcome Remarks from Conference Director

Gemma Smith, Senior Conference Director, Cambridge Healthtech Institute

 

8:10 Chairperson’s Opening Remarks

Dmitry Samarsky, PhD, CTO, Sirnaomics

 

8:15 Recent Advances with Antisense Technology at Ionis Pharmaceuticals

Monia_BrettBrett Monia, PhD, CEO, Ionis Pharmaceuticals


8:45 Increasing Gene Expression at Stoke Therapeutics

Kaye_EdwardEdward Kaye, MD, CEO, Stoke Therapeutics


9:15 FIRESIDE CHAT

Dmitry-SamarskyModerator: Dmitry Samarsky, PhD, CTO, Sirnaomics


Monia_BrettPanelists: Brett Monia, PhD, CEO, Ionis Pharmaceuticals


Kaye_EdwardEdward Kaye, MD, CEO, Stoke Therapeutics


10:00 Coffee Break in the Exhibit Hall with Poster Viewing

OPTIMIZING DESIGN, DELIVERY AND PERFORMANCE

10:45 Chairperson’s Opening Remarks

Dmitry Samarsky, PhD, CTO, Sirnaomics

10:50 Controlling Chirality of Phosphorothioates in Antisense Oligonucleotides Does Not Enhance Potency or Duration of Effect in the CNS

Brad Wan, PhD, Principal Scientist, Medicinal Chemistry, Ionis Pharmaceuticals

Bicyclic oxazaphospholidine (OAP) monomers were used to prepare a series of phosphorothioate (PS)-modified gapmer antisense oligonucleotides (ASOs) targeting Malat-1 or Lrrk2 mRNA. We found that controlling PS chirality in the MOE wings or in the DNA gap did not enhance ASO potency or duration of effect in the CNS relative to their stereo-random counterparts. Complete details including sequence, design of ASOs and lessons learned will be presented.

11:20 Control of Backbone Stereochemistry Provides a New Dimension for the Optimization of Oligonucleotide Drug Candidates

Chandra Vargeese, PhD, Senior Vice President, Drug Discovery, Wave Life Sciences

Wave Life Sciences has developed PRISMTM, our proprietary discovery and drug development platform, which enables us to generate stereopure oligonucleotides to target genetically defined diseases. Stereopure oligonucleotides are those in which the chiral configuration of backbone-modified oligonucleotides is precisely controlled at each linkage. We have demonstrated that, in addition to sequence and other chemical modifications, control over backbone stereochemistry provides an important new dimension for the optimization of oligonucleotide therapeutics. PRISM combines our unique ability to construct stereopure oligonucleotides with a growing knowledge of how the interplay among oligonucleotide sequence, chemistry and backbone stereochemistry impacts key pharmacologic properties. Using PRISM, we optimize stereopure oligonucleotides to meet pre-defined product profiles. We illustrate by example that optimized, stereopure oligonucleotides exhibit the desired activity across multiple modalities, for example those that depend on RNase H and those that promote exon skipping. We demonstrate that the potencies of stereopure oligonucleotides in cellular models under free-uptake conditions help predict their potencies in animal models. We also show that stereopure oligonucleotides can potently engage and durably impact the expression of their targets in animal models.

11:50 Learning from Failures: The Story of Drisapersen Exon Skipping Development for Duchenne Muscular Dystrophy

Annemieke Aartsma-Rus, PhD, Professor of Translational Genetics, Leiden University Medical Center

The aim of the antisense-mediated exon skipping therapy is to allow Duchenne patients to produce Becker-like dystrophins, hoping this will slow down disease progression. Antisense oligonucleotides (ASOs) will hide a target exon from the machinery, preventing its inclusion into mRNA. This restores the reading frame allowing the production of a partially functional dystrophin, as found in Becker muscular dystrophy patients. Currently, one exon skipping ASO has been approved for Duchenne therapy by the Food and Drug Administration, while another was not approved. The presentation will outline the development of this approach through proof-of-concept studies in cell and animal models, preclinical optimization studies and clinical trials, but also discuss the required multilateral education of stakeholders (patients, regulators and academics) to develop tools to measure clinical efficacy of the approach.

12:20 pm Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

12:50 Session Break

2:00 Arrowhead TRiM Platform in the Clinic

Mark Yen, PhD, Director, Clinical Development, Arrowhead Pharmaceuticals

This presentation will describe the safety and clinical effect with Arrowhead’s siRNA molecules in ongoing trials.

2:30 Industry Case Study from Quark Pharmaceuticals

Elena Feinstein, MD, PhD, CSO, Quark Pharmaceuticals

3:00 Sponsored Presentation (Opportunity Available)

3:30 Refreshment Break in the Exhibit Hall with Poster Viewing

4:15 Next-Generation Oligonucleotide Therapy Candidates with Tunable Backbones

David Tabatadze, PhD, President, ZATA Pharmaceuticals

The ZON platform is a novel class of oligonucleotides synthesized via phosphoramidite chemistry that permits facile attachment to the internucleoside phosphate charge-neutralizing groups (CNG) bearing positive charges at their termini. ZONs have length optimized CNG branches, allowing these positive charges to reach their neighboring phosphate groups where they can neutralize negative charges. ZON technology can be equally applied to DNA and RNA derivatives and be applied in all oligotherapy approaches.

4:45 Divalent siRNA Scaffold for Robust Gene Modulation in the Central Nervous System

Chantal Ferguson, Senior PhD Student, RNA Therapeutic Institute, University of Massachusetts Medical School

We developed a divalent (Di)-siRNA scaffold that supports potent and sustained gene silencing in the CNS upon intra-cerebroventricular (ICV) injection. Di-siRNAs are stabilized by 2’ modifications on every ribose, phosphorothioate backbone modifications, and substitution of the 5’ phosphate with metabolically stable 5’-(E)-vinyl phosphonate. In mice, di-siRNA silences target mRNA in mouse CNS for at least 6 months without detectable toxicity. In cynomologus macaques, a bolus injection of di-siRNA showed substantial distribution and robust silencing throughout CNS without detectable toxicity and minimal off-target effect.

5:15 Welcome Reception in the Exhibit Hall with Poster Viewing


6:15 Dinner Short Course Registration*

6:30 - 9:30 SC3: Oligonucleotides for Cancer Immunotherapy

Instructors:

Shanthi Ganesh, PhD, Associate Director, Preclinical Oncology, Dicerna Pharmaceuticals, Inc.

Weston Daniel, PhD, Senior Director Program Management, Exicure, Inc.

Additional Instructors to be Announced

*Separate registration required.

WEDNESDAY, MARCH 18

8:00 am Breakfast Breakout Roundtable Discussions

MACHINE LEARNING-GUIDED DRUG DESIGN

9:15 Chairperson’s Remarks

Ekkehard Leberer, PhD, Senior Director, R&D Alliance Management, Sanofi; Scientific Managing Director, COMPACT Consortium

9:20 Machine Learning-Guided Design of Antisense Oligonucleotides

Peter Hagedorn, Senior Principal Scientist and Team Leader of Bioinformatics and RNA Biology, Roche Innovation Center Copenhagen

Antisense oligonucleotides are well-suited for machine learning-guided drug design. As oligomers, they can be represented digitally using well-established methods from biological sequence analysis, and any computationally predicted design is straightforward to synthesize using standard phosphoramidite building blocks. Recent examples of machine learning-guided drug design, enabled by careful organization and labeling of preclinical datasets across multiple discovery projects, as well as by investments in laboratory automation that allows cellular assays to be run in high-throughput, will be presented.

RECENT ADVANCES WITH RNAs

9:50 FEATURED PRESENTATION: MiRNA Therapeutics: From Bench to Bedside

Ekkehard Leberer, PhD, Senior Director, R&D Alliance Management, Sanofi; Scientific Managing Director, COMPACT Consortium

The non-coding genome makes up 98.8% of the human genome. Most of this non-coding genome is transcribed into non-coding RNAs that may play an important role in cellular regulation in health and disease; these non-coding RNAs could be novel targets for future medicines. MicroRNAs are short non-coding RNAs that regulate biochemical pathways and networks of pathways by the mechanism of RNA interference (RNAi). MicroRNA-21 has been implicated in multiple organs as a microRNA associated with fibrotic diseases and cancer. The presentation will summarize the opportunities and challenges of developing microRNA-based drugs, discuss challenges and solutions for delivery to target tissues, and will illustrate the successful generation of an anti-fibrotic microRNA-based therapeutic approach by targeting microRNA-21 with an antisense oligonucleotide (anti-miR-21). The presentation will illustrate the drug development path from the identification of miRNA-21 as a therapeutic target in fibrosis up to the entry of the anti-miR-21 drug into Phase II clinical trial for a genetic fibrotic kidney disease called Alport Syndrome.

10:20 Sponsored Presentation (Opportunity Available)

10:50 Coffee Break in the Exhibit Hall with Poster Viewing

11:35 How Do miRNAs and RNAi Function Inside Cells?

David Corey, PhD, Professor, Department of Pharmacology, UT Southwestern

RNA interference can be a potent regulatory mechanism in human cells. Synthetic RNAs can control gene expression and have been developed to be successful drugs while endogenous miRNAs can control natural physiologic processes and disease. Despite two decades of study, however, the full scope of natural RNAi in cells has remained obscure. Our results suggest that the action of miRNAs in cells is complex and must be justified with care.

12:05 pm Development of Lipid Nanoparticles for mRNA-Based Therapeutics

Kerry Benenato, PhD, Senior Director, Discovery Chemistry, Moderna

The development of mRNA delivery vehicles for therapeutics is challenging. To start, the delivery vehicle must be able to protect the mRNA from degradation, shield the mRNA from the immune system and release its cargo in a tissue and cell specific manner. We have found parallel optimization of the mRNA chemistry and the lipid nanoparticle delivery vehicle is integral to the solution to each challenge. This effort has resulted in a drug product which affords high level of protein expression with an optimized pharmacokinetics and a clean tolerability profile. This presentation will highlight some of the important structure activity relationships of the lipid nanoparticle chemistry and key factors in the design of a delivery system which enables safe repeat dosing in non-human primates.

12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:05 Dessert Break in the Exhibit Hall with Poster Viewing

1:50 Advancing siRNA Drug Delivery to Enhance RNAi Cancer Therapy

Patrick Lu, PhD, President & CEO, Sirnaomics

2:20 PANEL DISCUSSION: Opportunities and Challenges with RNAs

Moderator: Ekkehard Leberer, PhD, Senior Director, R&D Alliance Management, Sanofi; Scientific Managing Director, COMPACT Consortium

Panelists: Patrick Lu, PhD, President & CEO, Sirnaomics

Kerry Benenato, PhD, Senior Director, Discovery Chemistry, Moderna

David Corey, PhD, Professor, Department of Pharmacology, UT Southwestern

3:05 Networking Refreshment Break

CLOSING PLENARY

3:35 Chairperson’s Remarks

Chairperson to be Announced

3:40 Biological Activity of Thiomorpholino Oligonucleotides

Marvin Caruthers, PhD, Distinguished Professor, University of Colorado

Thiomorpholino oligonucleotides are analogues containing morpholino- and 2’deoxyribonucleosides joined through thiophosphor internucleotide linkages. These analogues stimulate biological activity in a dual luciferase assay, in exon skipping with Marfan Syndrome and Duschenne Muscular Dystrophy, and in regulating TUG 1 RNA. Current research includes regulating microRNA maturation, editing transcription termination, exon skipping of additional genetic diseases, and antisense experiments with RNase H.

4:10 Talk Title to be Announced

Speaker to be Announced, Alnylam Pharmaceuticals

4:40 Close of Oligonucleotide Discovery and Delivery


4:40 Dinner Short Course Registration*

5:00 - 8:00 SC4: Gene Editing for Targeted Therapies

Instructors:

Clifford Steer, MD, Professor of Medicine and Genetics, Cell Biology, and Development; Director, Molecular Gastroenterology Program, University of Minnesota Medical School

Khalid Shah, MS, PhD, Director, Center for Stem Cell Therapies and Imaging, Harvard Medical School; Vice Chair of Research, Brigham and Women’s Hospital

Additional Instructors to be Announced

*Separate registration required.

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