Cambridge Healthtech Institute’s 7th Annual

Oligonucleotide Discovery and Delivery

Optimizing Design, Delivery and Performance

March 15 - 16, 2022 EDT

Cambridge Healthtech Institute’s Oligonucleotide Discovery and Delivery conference reveals the latest in oligonucleotide discovery, chemistry and delivery, with in-depth sessions on new chemistries, targeted delivery mechanisms and important preclinical and clinical advances. The talks given by leading scientists focus on developments in mRNA, antisense, siRNA, aptamers, conjugates and other new oligo modalities paving the way for the next generation of targeted oligonucleotide therapeutics.

Tuesday, March 15

7:30 am Short Course Registration & Morning Coffee (Gallery Foyer)
8:00 am Recommended Pre-Conference Short Course*
SC1: Examining the Safety and Toxicity of Nucleic Acid Therapeutics (Salada)

*All Access Premium Pricing or separate registration required. See short course page for details.

9:15 am Main Conference Registration (Gallery Foyer)
10:15 am Organizer's Welcome Remarks

Tanuja Koppal, PhD, Senior Conference Director, Cambridge Healthtech Institute

ROOM LOCATION: Singlo

ADVANCES IN TARGETED DELIVERY

10:25 am

Chairperson's Opening Remarks

Dmitry Samarsky, PhD, CTO, Sirnaomics
10:30 am

mxRNA: Miniaturized RNAi Triggers Composed of Single Oligonucleotides

Dmitry Samarsky, PhD, CTO, Sirnaomics

Sirnaomics has developed proprietary GalNAc-RNAi therapeutic platform – GalAhead, with mxRNA comprising one of its key technological components. mxRNAs (or miniaturized RNAi triggers) are composed of single 31-33 nt long oligonucleotides, demonstrating excellent activity in primary hepatocytes (in vitro) and in mice (in vivo). In addition to the experiments in vitro and with rodents, we will present results of our 13-week study in non-human primates conducted with the candidate molecule for our frontrunner GalAhead therapeutic program.

11:00 am

Development of a GalNAc-asiRNA Platform for Treatment of Liver Disorders

Behfar Ardehali, PhD, Senior Scientist, OliX Pharmaceuticals

To address the unmet needs in treatment of liver disorders caused by overabundance of hepatocyte factors, OliX Pharmaceuticals has developed a N-acetyl galactosamine (GalNAc) conjugation platform for high-efficiency, ASGPR-mediated delivery of asiRNA compounds to hepatocytes. We have also established dynamic discovery and preclinical stage programs to target multiple hepatic disorders, among them, Nonalcoholic steatohepatitis (NASH) and HBV. Here we present the latest advancements in our liver programs.

11:30 am

Exploring Chemical Space for Improving Properties of RNA Therapeutics

Thazha Prakash, PhD, Executive Research Fellow, Ionis Pharmaceuticals, Inc.

Advancements in the chemical design of oligonucleotide drugs have improved potency, safety and duration leading to better clinical outcomes. Efforts to expand the boundaries of existing chemical space to further enhance the properties of RNA therapeutics will be presented.

12:00 pm Session Break
Marvin Caruthers, PhD, Distinguished Professor, Biochemistry, University of Colorado

Thiomorpholino oligonucleotides (TMOs) and their DNA chimeras are new analogues containing morpholino- and 2’-deoxyribonucleosides joined through thiophosphoramidate internucleotide linkages. The TMO and TMO/DNA chimeras were observed to have higher melting temperatures when compared to natural DNA/DNA and DNA/RNA duplexes and are active with RNase H1. These analogues are efficiently taken up by cells and stimulate biological activity in primary cells as well as various established cells lines. Current research underway in over 20 collaborations are focused primarily on rare and fatal genetic diseases. The lecture will focus on results from Duschenne Muscular Dystrophy, Niemann-Pick type C1 and regulating the maturation of TUG 1 and TERT RNA. 

12:40 pm Session Break
1:15 pm

Chairperson's Opening Remarks

Leo Ziqing Qian, PhD, Co-Founder & Vice President, Discovery Research, Entrada Therapeutics
1:20 pm

Delivery of RNA Therapeutics: The Great Endosomal Escape

Steven Dowdy, PhD, Professor, Department of Cellular & Molecular Medicine, University of California San Diego School of Medicine

RNA therapeutics have great potential to selectively treat human disease, especially cancer, COVID and neurological disorders.  However, due to their 8-14 kiloDalton size and 20-40 negatively charged phosphates, RNAs have limited (<1%) to no ability to overcome a billion years of evolutionary defenses that prevent RNAs from escaping across the endosomal lipid bilayer membrane into the cytoplasm of cells.  Consequently, endosomal escape remains The Technological Problem to solve for wide-spread development of RNA therapeutics. 

1:50 pm

Development of Endosomal Escape Vehicles to Enhance the Intracellular Delivery of Oligonucleotides

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

We have developed a novel oligonucleotide delivery platform by conjugation with Entrada’s proprietary Endosomal Escape Vehicle (EEV), a class of cyclic peptides designed to facilitate intracellular delivery and endosomal escape. The preclinical results have confirmed the significant therapeutic potential of the strategy for DMD and demonstrated that the EEV platform can serve as a general and highly efficient delivery technology for the extrahepatic delivery of therapeutic oligonucleotides.

2:20 pm Sponsored Presentation (Opportunity Available)
2:50 pm Refreshment Break in the Exhibit Hall with Poster Viewing (Bohea)

FEATURED SESSION: EMERGING OLIGO THERAPIES

3:30 pm

Chairperson's Opening Remarks

Jonathan Watts, PhD, Associate Professor, RNA Therapeutics Institute, University of Massachusetts Chan Medical School
Nagy Habib, ChM, FRCS, Head of R&D and CMO, MiNA Therapeutics Ltd.

Small activating RNAs (saRNA) are double stranded 21 nucleotide RNA that either target promoters or enhance genes leading to mRNA upregulation. saRNAs can be delivered with liposomes into the systemic circulation or subcutaneously by conjugation with aptamers or GalNAC.  MTL-CEBPA is an investigative drug that resulted from the conjugation of saRNA CEBPA with NOV 340 lipsomes that targets tumour associated macrophages, in order to favorably alter the tumor microenvironment.  MTL-CEBPA has been administered safely in over 100 patients with advanced cancer and improved clinical outcome in a sub-set of patients when co-administered with TKI or check point inhibitor.

Luke Koblan, PhD, Former Graduate Student, Laboratory of David Liu, Department of Chemistry and Chemical Biology, Harvard University and Broad Institute of MIT and Harvard

Base editors hold significant promise to precisely correct the underlying genetic cause of many diseases. Correcting pathogenic mutations in disease-relevant contexts has remained challenging due to low editing efficiencies and limited editor delivery modalities. Systematic improvements to base editor performance and delivery enabled efficient adenine base editor-mediated correction of the predominant mutation underlying Hutchinson-Gilford Progeria Syndrome in a mouse model of this disease, ultimately rescuing major hallmarks of disease pathology.  

Jonathan Watts, PhD, Associate Professor, RNA Therapeutics Institute, University of Massachusetts Chan Medical School

We describe progress toward complete chemical modification of CRISPR guides and their in vivo genome editing activity. We have identified patterns of backbone and sugar modifications that allow robust gene editing activity in mRNA and RNP formats, in vitro and in vivo.  We also describe a broadly accessible modification strategy for DNA donors used as templates for homology-directed repair, which improves the efficiency of HDR up to 8-fold over normal DNA donors.

Paloma H. Giangrande, PhD, Vice President, Platform and Discovery Sciences Biology, Wave Life Sciences

The talk will cover proof-of-concept preclinical in vivo data demonstrating effective and durable editing of human SERPINA1 Z allele mRNA in the liver, resulting in a therapeutically meaningful increase in circulating, functional wild-type AAT protein. These initial in vivo studies utilize Wave’s proprietary transgenic mouse model, which has both the human SERPINA1 Z-allele as well as human ADAR that is expressed comparably to human cells.

5:35 pm Welcome Reception in the Exhibit Hall with Poster Viewing (Bohea)
6:35 pm Close of Day

Wednesday, March 16

7:30 am Registration Open (Gallery Foyer)

ROOM LOCATION: Singlo

BREAKFAST INTERACTIVE DISCUSSIONS

8:00 am Breakfast Interactive Discussions

Interactive Discussions are informal, moderated discussions, allowing participants to exchange ideas and experiences and develop future collaborations around a focused topic. Each discussion will be led by a facilitator who keeps the discussion on track and the group engaged. For in-person events, the facilitator will lead from the front of the room while attendees remain seated to promote social distancing. For virtual attendees, the format will be in a Zoom room. 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 Interactive Discussion page on the conference website for a complete listing of topics and descriptions. 

INTERACTIVE DISCUSSION: Innovations in Oligo Design & Delivery

Isabel Aznarez, PhD, Vice President, Discovery Research, Stoke Therapeutics
Thazha Prakash, PhD, Executive Research Fellow, Ionis Pharmaceuticals, Inc.
Arthur M. Krieg, Founder & CSO, Checkmate Pharmaceuticals
  • Advancements in chemical design for oligonucleotide drugs
  • Advancements in targeted delivery for oligonucleotide drugs
8:45 am Session Break

OLIGO DRUGS FOR DIVERSE DISEASE INDICATIONS

8:55 am

Chairperson's Opening Remarks

Eric P Van der Veer, PhD, CSO, Hybridize Therapeutics BV
9:00 am

A Novel, RNA-Based Anti-Viral Approach to Limit BK Virus Propagation in Immunocompromised Patients

Eric P Van der Veer, PhD, CSO, Hybridize Therapeutics BV

BK virus (BKV) is a universal latent renal virus that reactivates in kidney transplantation patients and can lead to graft loss. No treatment exists for combatting BK virus. As such, treatment options for BKV are vital. At Hybridize, we have developed an innovative RNA-based direct-acting antiviral strategy that prevents BKV-mediated disease.

9:30 am

Self-Delivering FANA ASO Targeting Human FOXP3 For Cancer Immunotherapy

Wayne W. Hancock, MD, PhD, Professor of Pathology & Lab Medicine, University of Pennsylvania and Children's Hospital of Philadelphia

The benefits of immunotherapy are often limited by an immunosuppressive environment at the tumor site involving T-regulatory (Treg) and myeloid-derived suppressive cells. We developed self-delivering FANA antisense oligonucleotides (ASO) against human FOXP3 that were screened for their ability to knockdown FOXP3 and decrease human Treg suppressive function in vitro. Selected FANA were then tested in immunodeficient NSG mice reconstituted with human PBMC and shown to knockdown human FOXP3 in vivo. We also developed FANA ASO against murine Foxp3 that knocked-down Foxp3 mRNA and protein expression in vitro and in vivo, decreased Treg suppressive function and inhibited tumor growth in syngeneic lung tumor models. In summary, we have developed highly efficacious FANA ASO lead candidates that can knockdown FOXP3, inhibit Treg function and promote antitumor immunity and are proceeding with IND-enabling studies.

Ryan Donnelly, Business Unit Manager - Research Reagents, Horizon Discovery

Multiple siRNA, ASOs, and now antibody-oligo conjugates (AOCs) have moved into the clinic, what will be next? Overview of synthesis chemistry from Dharmacon including methods for conjugation and complex modification patterns to support your research – from screening to scale up.

10:15 am Coffee Break in the Exhibit Hall with Poster Viewing (Bohea)
11:10 am

MicroRNA Therapeutics: Targeting Fibrotic Diseases

Ekkehard Leberer, PhD, Senior Life Sciences Consultant, ELBIOCON; Scientific Managing Director, COMPACT Consortium

MicroRNAs are short non-coding RNAs that regulate biochemical pathways by RNA interference (RNAi). Dysregulation of microRNAs is associated with many diseases including fibrosis. The presentation shows the development of anti-fibrotic therapeutic strategies using anti-miRs as therapeutic molecules.

11:40 am

A GalNAc-MCJ siRNA as a Novel Mitochondrial Regulator for Treating NASH

Cynthia M. Arbeeny, PhD, CSO, Mitotherapeutix LLC

Mitotherapeutix has identified MCJ/DNAJC15, a novel negative regulator of mitochondrial metabolism, as a key target to treat NASH and other metabolic diseases. We have performed SAR and selected a lead GalNAc-MCJ siRNA as a clinical candidate for NASH. Treatment targets hepatocytes and effectively knocks down MCJ reducing disease severity in NASH models. Activity has been confirmed in non-human primates. Preclinical toxicology and PK/PD studies are planned to support an IND-filing.

12:10 pm Enjoy Lunch on Your Own
12:50 pm Dessert Break in the Exhibit Hall with Poster Viewing (Bohea)

KEYNOTE SESSION: OLIGO THERAPIES – OPPORTUNITIES & CHALLENGES

1:25 pm

Chairperson's Opening Remarks

Isabel Aznarez, PhD, Vice President, Discovery Research, Stoke Therapeutics
1:30 pm KEYNOTE PRESENTATION:

A Novel RNA-Based Approach to Treat Genetic Diseases

Isabel Aznarez, PhD, Vice President, Discovery Research, Stoke Therapeutics

Targeted augmentation of nuclear gene output (TANGO) is a novel technology that exploits antisense oligonucleotide (ASO)-mediated modulation of pre-mRNA splicing to increase full length, fully functional protein expression. In haplo insufficiencies; e.g. Dravet syndrome and autosomal dominant optic atrophy, TANGO ASOs increase protein expression by leveraging the wild type allele. TANGO can be employed to target a wide range of gene types, functions and sizes to address genetic diseases amenable to protein upregulation.

2:00 pm KEYNOTE PRESENTATION:

RNA Targeting Progress in Severe and Rare Disease

Richard Geary, PhD, Chief Development Officer and Executive Vice President, Antisense Drug Development, Ionis Pharmaceuticals, Inc.

More than ten RNA targeted products have been approved and launched in the rare and severe disease space.  Both increase and decrease in protein target production have been utilized with RNA engaging oligonucleotides.  Pipeline progress will be summarized along with the challenges and opportunities that have become apparent as the research continues.

2:30 pm Refreshment Break in the Exhibit Hall & Last Chance for Poster Viewing (Bohea)
3:10 pm KEYNOTE PRESENTATION:

Intratumoral Delivery of a CpG-A TLR9 Agonist Using a Virus-Like Particle Can Overcome Resistance to PD-1 Blockade in Patients with Advanced Melanoma

Arthur M. Krieg, Founder & CSO, Checkmate Pharmaceuticals

Innate immune activation is an appealing approach to overcoming resistance to PD-1 blockade in patients with advanced cancer, and yet positive results in murine tumor models have usually not translated into human clinical data. CpG-A TLR9 agonists have unique immune effects that are enhanced by delivery using an immunogenic virus-like particle, leading to enhanced systemic anti-tumor effects in preclinical models and in humans.

3:40 pm KEYNOTE PRESENTATION:

Engineering Antibody Oligonucleotide Conjugates (AOCs): Taking Receptor-Mediated Uptake One Step Further

Arthur Levin, PhD, CSO, Avidity Biosciences

The promise of oligonucleotide therapeutics is to use Watson-Crick-Franklin base-pairing rules to design drugs directly and rationally based on genomic information. Until recently, that promise has remained elusive because of cell barriers to oligonucleotide uptake. Receptor-mediated uptake through bioconjugation oligonucleotides has changed that. Avidity’s AOC technology uses monoclonal antibodies to cell surface proteins that are internalized in order to facilitate the functional delivery of oligonucleotide therapeutics into a broad range of cell and tissue types. 

4:10 pm KEYNOTE PRESENTATION:

Harnessing Endogenous Retroviral-Like Proteins for RNA Delivery

Michael Segel, PhD, Postdoctoral Fellow, Laboratory of Dr. Feng Zhang, Broad Institute of MIT and Harvard

Retroelement derived proteins are scattered throughout the human genome. One such protein, the retroviral-like Gag protein PEG10, can be harnessed to facilitate efficient intercellular delivery of cargo RNAs in mammalian cells.

4:40 pm Close of Conference
9:00 am

A Novel, RNA-Based Anti-Viral Approach to Limit BK Virus Propagation in Immunocompromised Patients

Eric P Van der Veer, PhD, CSO, Hybridize Therapeutics BV

BK virus (BKV) is a universal latent renal virus that reactivates in kidney transplantation patients and can lead to graft loss. No treatment exists for combatting BK virus. As such, treatment options for BKV are vital. At Hybridize, we have developed an innovative RNA-based direct-acting antiviral strategy that prevents BKV-mediated disease.






Call For Papers