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

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

The development of antisense technology as a novel drug discovery platform to treat a broad range of rare and common diseases is now validated.  Antisense medicines offer tremendous hope for patients afflicted with serious diseases that cannot be addressed with traditional drug discovery platforms.  With numerous antisense medicines recently receiving market authorization along with a large and diverse pipeline of medicines on the horizon, antisense is poised to revolutionize the practice of medicine for generations. 

8:45 Using ASOs to Upregulate Protein Expression

Kaye_EdwardEdward Kaye, MD, CEO, Stoke Therapeutics

Stoke has developed an RNA platform that efficiently upregulates protein expression. This is accomplished by removing retained non-coding elements at the pre-mRNA level and thereby increasing the amount of full-length mRNA.  This increase in full length mRNA from a normal copy of the gene results in an increase of full-length protein which we are using to address haplo-insufficient diseases. 

9:15 FIRESIDE CHAT: The Future Outlook of RNA Targeted Therapeutics 

  • Recent breakthroughs and advancements in RNA therapeutics and gene editing/expression
  • Opportunities of neurological diseases in drug discovery, development and delivery
  • Challenges that lie ahead

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

Wan_BradBrad 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

Vargeese_ChandraChandra 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

Aartsma-Ru_Annemieke_micAnnemieke 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

Yen_MarkMark Yen, MD, 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

Feinstein_ElenaElena 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

Tabatadze_DavidDavid 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

Ferguson_ChantalChantal 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.

Sushma Gurumurthy, PhD, Associate Director, Oncology Research, Moderna


*Separate registration required.

WEDNESDAY, MARCH 18

8:00 am Breakfast Breakout Roundtable Discussions

Enjoy a continental breakfast and join us for a moderated roundtable discussion with interactive problem solving. These sessions bring together attendees from diverse backgrounds to exchange ideas and develop future collaborations around a focused topic, in an informal environment.

TABLE 1: Adoption and Implementation of Innovative Technologies Used in Discovery and Delivery

Marvin Caruthers, PhD, Distinguished Professor, University of Colorado


TABLE 2: Considerations When Developing Splice Modulating Therapies

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

  • Developing splice modulating therapies for small patient numbers
  • Selecting model systems and controls for pre-clinical exon skipping tests
  • Deciding when to move from pre-clinical to clinical studies
  • Involve patients in therapy development and trial design


TABLE 3: Oligonucleotide Drug Discovery: From the Drawing Board to the Clinic

Moderator: Troels Koch, PhD, CTO, SVP Science & Technology, IneXos Therapeutics

Drug discovery is an exceptionally complex undertaking. What is of paramount importance is that the initial steps in the process are conducted as well-informed and qualified as possible. We will discuss drug discovery fundamentals and try to identify how an “ideal” program would look like. Discussion points:
• Delivery - target – modality triangulation: Where to begin, any preference?
In vitro and in vivo assays: Toxicity and potency validation – Establish the right controls and secure high degree of translation
• How to make the best selection of target and indication to favor oligonucleotide therapeutics in relation to competing modalities?
• Advancing in silico discovery: Going beyond sequence based bioinformatics with structure based quantum mechanical modelling?

 

TABLE 4: Examining the Safety and Toxicity of Nucleic Acid Therapeutics

Moderator: Steven Kates, PhD, VP, Regulatory Affairs, Dicerna Pharmaceuticals

  • What tox studies are needed and when?
  • How to assess your impurities (analytical methods)
  • Discussing mutagenicity
  • Examining ADA assays


TABLE 5: Adoption and Implementation of Innovative Technologies Used in CMC And Manufacturing

Moderator: Roumen Radinov, PhD, Director Process Chemistry, Alnylam Pharmaceuticals

  • The solid phase oligonucleotide synthesis based on sequential coupling of phosphoramidite monomers is a well-established industrial manufacturing process
  • Currently performed routinely on kilo scale mainly due to limitations of the current synthesis and purification processes
  • Novel approaches will need to be designed and developed to support high-volume oligonucleotide drugs in the near future
  • Participants are invited to share their insights and experience in the development of alternative synthesis and purification technologies with potential for the cost-effective ton scale manufacture of oligonucleotides


TABLE 6: CMC Regulatory Hurdles in Rare Disease

Moderator: Kimberly Tyndall, Principle, CMC Tyndall Consultant

  • How to successfully proceed
  • Never a marketed product N=1
  • Overcoming CMC hurdles
  • Why

 

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

Hagedorn_PeterPeter 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

Leberer_Ekkehard-001Ekkehard 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 Asymmetric siRNAs Targeting Age-Related Macular Degeneration

Lee_Dong-kiDong-Ki Lee, PhD, CEO, OliX Pharmaceuticals

OliX pharmaceuticals is developing novel RNAi therapeutics against a variety of diseases with unmet medical needs, based on its proprietary asymmetric siRNA (asiRNA) platform. In this presentation, we will introduce preclinical data from OLX301A and 301D, ocular asiRNA therapeutic programs targeting age-related macular degeneration (AMD). 

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

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

Corey_DavidDavid 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

Benenato_KerryKerry 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 Novel siRNA Therapeutics for Enhancing Antitumor Activity of Immune Checkpoint Inhibitor   

Lu_PatrickPatrick Lu, PhD, President & CEO, Sirnaomics

Using a proprietary and optimized polypeptide nanoparticle (PNP) -based delivery technology, we have developed the novel anti-fibrosis and anti-cancer therapeutics with siRNAs targeting both TGFβ1 and Cox-2 simultaneously (STP705), resulting in human fibroblasts apoptosis. STP705 was initially used for local treatments for skin hypertrophic scar and non-melanoma skin cancer. STP707 (a systemic formulation of STP705) was further advanced for treatment of liver fibrosis and cholangiocarcinoma, both of these indications have received Orphan drug designations by US FDA. I will discuss the unique advantage using our PNP technology platform for safe and efficient siRNA delivery, and our strategy for advancing multiple clinical studies ongoing in both USA and China. 

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

CaruthersMarvin 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 GIVLAARI™: Story of the First-Ever Approved GalNAc-Conjugate RNAi Therapeutic, for Acute Hepatic Porphyria

Simon_AmyAmy Simon, MD, Executive Director, Clinical Research, 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, M.D., Professor of Medicine and, Genetics, Cell Biology, and Development, University of Minnesota Medical School
Branden Moriarity, PhD, Assistant Professor, Department of Pediatrics, 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

Jonathan Gootenberg, PhD, McGovern Fellow, McGovern Institute for Brain Research, MIT

Omar Abudayyeh, PhD, McGovern Fellow, McGovern Institute for Brain Research, MIT

 

*Separate registration required.

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