Cambridge Healthtech Institute’s Third Annual

Oligonucleotide Discovery and Delivery

Advances in the Development and Delivery of Aptamer, Antisense and RNA Therapeutics

March 26-28, 2018 | Boston Marriott Cambridge | Cambridge, MA

Oligonucleotide-based therapeutics have long been considered as forming the third major drug development platform specifically focused on modulating gene expression by targeting RNA transcripts or the genome itself. A key distinguishing attribute of utilizing nucleic acids as therapeutic agents is their ability to access the “undruggable” space left by small molecules and biologics, allowing drug developers to address disease areas currently with limited or no therapeutics options. However, first- and second-generation molecules exhibiting potency and safety issues have hindered the potential of oligonucleotide therapies dramatical impacting the drug development landscape. Recent advances in nucleic acid medicinal chemistry and delivery have led to the creation of a new generation of oligonucleotide therapies harnessing chemical modifications and conjugations to improve their stability, bioavailability, specificity and potency. These advances, along with a robust development landscape, and several late-stage clinical products poised for approval, have led to a sharp resurgence of interest in the discovery of oligonucleotide-based therapeutics.

Due to the remarkable success of the event, Cambridge Healthtech Institute is delighted to host the Third Annual Oligonucleotide Discovery and Delivery conference, March 26-28, in Cambridge, MA. Join leading oligonucleotide developers and discovery scientists to discuss technological and scientific advances in nucleic acid synthesis, medicinal chemistry and delivery, as well as preclinical and clinical findings.

Final Agenda

Monday, March 26

7:00 am Registration and Morning Coffee


8:00 Welcome Remarks from Cambridge Healthtech Institute 

8:10 Chairperson’s Opening Remarks

Muthiah (Mano) Manoharan, PhD, Senior Vice President, Drug Discovery, Alnylam Pharmaceuticals, Inc.

8:15 GalNAc-Conjugated siRNAs as a New Paradigm in Oligonucleotide Therapeutics

Muthiah_ManoharanMuthiah (Mano) Manoharan, PhD, Senior Vice President, Drug Discovery, Alnylam Pharmaceuticals, Inc.

During this presentation, I will discuss the progress in the advancement of RNAi therapeutics and review delivery of RNAi and where the field is going. I will also discuss conjugated delivery of oligonucleotides to the liver and combining novel chemical modifications with conjugation strategies.

8:45 mRNA as Medicine

Melissa Moore Ph.D., Chief Scientific Office, mRNA Research Platform, Moderna Therapeutics

Messenger RNAs (mRNAs) show tremendous promise as a novel therapeutic modality, allowing for creation of prophylactic and therapeutic vaccines as well as medicines for treating inborn metabolic disorders. I will discuss our recent progress in identifying new formulations for the delivery of mRNA vaccines versus mRNA therapeutics.

9:15 Highly Effective Design and Validation of Antisense Oligonucleotides (AON) for Research and Therapeutic Applications

Ernesto Guccione, PhD, Senior Faculty, Oncological and Pharmacological Sciences, Mount Sinai; Principal Investigator, A*STAR

Antisense oligonucleotides (AON) are a powerful research and therapeutic tool. In fact, their use has been instrumental to researchers to uncover genes and exons’ functions, as well as to treat previously incurable diseases. I will discuss an example of the research use of AONs to dissect the function of alternatively splicing in prostate cancer. We analysed TCGA datasets mining for differences in alternative splicing between normal and cancer tissues. The top hit was represented by the RNA binding protein MBNL1 exon 7, consistently more included in mature mRNA of tumour samples compared to normal prostate. With effective and selective AONs we were able to modulate exon 7 inclusion in cancer cell lines, demonstrating how MBNL1 delta7 alters the mRNA stability of genes linked to migration, cell cycle arrest, DNA-damage repair and mitotic chromosome segregation. The same approach, thanks to our AON's design algorithm, can be applied to a vast number of alternative splicing events. In fact, AON-mediated modulation of the splicing pattern of key genes in androgen sensitive vs androgen resistant prostate cancer lines, is sufficient to significantly affect migration and survival of these cells. The use of AONs to modulate splicing goes beyond the use in research. Immunotherapy with TCR-redirected T cells to treat HBV-positive hepatocellular carcinoma (HCC) is now in clinical trials. T cells from patients are expanded ex-vivo and transduced with an HBV-specific TCR mRNA. We demonstrate that AONs targeting immuno-suppressive genes (e.g. PD1, CTLA4, TIM3) offer a potential avenue to improve killing efficiency of the target tumor cells, opening important therapeutic options in the growing field of immunotherapy.

9:45 Networking Coffee Break


10:30 Temporary Inhibition of p53 for Tissue Protection: from Therapeutic Concept to Prevention of Acute Kidney Injury Following Kidney Transplantation and Cardiac Surgery

Elena_FeinsteinElena Feinstein, MD, PhD, CSO, Quark Pharmaceuticals

Although therapeutic inhibition of the master tumor suppressor p53 is counterintuitive, its temporary inhibition for tissue protection under conditions of genotoxic and/or oxidative stress was proven not only safe but also efficient. Using an siRNA compound targeting p53, we have achieved efficacy proof-of-concept (POC) in the animal models of ischemia-reperfusion and toxic kidney injury as well as in the model of chemotherapy-induced hair loss. Clinical POC was achieved in two large multicenter double-blinded placebo-controlled Phase 2 trials studying efficacy of QPI-1002, a p53-targeting siRNA compound, in prevention of delayed graft function following kidney transplantation and of acute kidney injury following cardiac surgery.

11:00 Sarepta’s Exon Skipping PMO-ASOs

Marco Passini, PhD, Senior Director, Biology, Sarepta Therapeutics

Phosphorodiamidate morpholino oligomers (PMOs) are uncharged single-stranded oligonucleotides that bind to target RNAs to modulate activity. Cell penetration has been cited as a challenge for PMOs to reach their full potential. Delivery into cells and overall activity of these oligomers can be improved by chemically modifying the PMO by modifying internucleoside linkage(s) or by adding a cell-penetrating peptide (PPMO). A series of proprietary classes of compounds that includes PPMO, PMO-X® and PMOplus® are being developed by Sarepta Therapeutics that have the potential to treat a wide variety of indications including Duchenne muscular dystrophy, neuromuscular and neurodegenerative diseases.

11:30 Development of Stereopure Nucleic Acid Therapeutics

Chandra_VargeeseChandra Vargeese, PhD, Senior Vice President and Head, Drug Discovery, WAVE Life Sciences

WAVE Life Sciences is utilizing its innovative and proprietary synthetic chemistry drug development platform to design, develop and commercialize stereopure nucleic acid therapeutics that precisely target the underlying cause of rare genetic diseases, delivering exceptional treatment options for patients. Given the unique versatility of its chemistry platform, WAVE’s pipeline will span multiple oligonucleotide modalities including antisense, exon-skipping and single-stranded RNAi.

12:00 pm Enjoy Lunch on Your Own


1:25 Chairperson’s Remarks

Gunnar J. Hanson, PhD, Senior Director, Research Chemistry, Sarepta Therapeutics, Inc.

1:30 Breakthrough Innovation in Phosphorodiamidate Morpholino Oligomer (PMO) Delivery Chemistry

Gunnar_HansonGunnar J. Hanson, PhD, Senior Director, Research Chemistry, Sarepta Therapeutics, Inc.

Phosphorodiamidate morpholino oligomers (PMOs) enable Watson-Crick binding to pre-mRNA in the nucleus and thereby enable the control of new definitions of intron-exon junctions within the spliceosome. Such splice alteration is limited by the efficiency of PMO delivery into the cytosol and nucleus. To solve this 40-year old delivery problem, new cell-penetrating peptides (CPPs) were designed, which by covalent attachment to PMOs, dramatically enhance the delivery of these macromolecules into the cytosol and nucleus.

2:00 Stereodefined Phosphorthioate LNA Oligonucleotides

Nanna_AlbaekNanna Albaek, PhD, Principal Scientist and Group Leader of New Chemistry, Roche Pharma Research and Early Development, Roche Innovation Center Copenhagen

The continuous refinement and development of the LNA oligonucleotide drug discovery platform has lead to utilizing the improvements induced by introducing fully stereopure LNA oligonucleotides. Phosphorthioate (PS) backbone oligonucleotides have for a long time been used as diasteremeric mixtures in drug discovery for improved properties such as stability and biodistribution. By defining the PS stereochemistry improvements of eg. potency and tolerability are found compared to the diastereomeric mixture.

2:30 The GLP1 Receptor for Targeted Delivery of Antisense Oligonucletoides to Pancreatic ß-Cells

Thazha_PrakashThazha P. Prakash, Executive Research Fellow, Ionis Pharmaceuticals

Antisense oligonucleotide (ASO)-based drug development is evolving as an effective therapeutic approach. To fully realize the potential of this technology, it is necessary to improve the potency of ASOs in extrahepatic tissues. Inability to selectively deliver antisense therapies to ß-cells is a substantial barrier to the development of innovative and safe treatments for ß-cell specific diseases. Here, we used a GLP1 receptor (GLP1R) peptide agonist conjugated to ASO to explore the concept of delivering ASO using GLP1R mediated internalization. We show that the GLP1 receptor can be used as a targeting approach for efficient and selective delivery of ASO to pancreatic ß-cells in cells and in animals.

3:00 Refreshment Break in the Exhibit Hall with Poster Viewing


3:45 Natural Selection: The Evolution of siRNA Delivery at Arrowhead Pharmaceuticals

James_HamiltonJames C. Hamilton, MD, MBA, Vice President, Clinical Development, Arrowhead Pharmaceutical Inc.

Results from animal and human studies using multiple different delivery technologies have driven the evolution and optimization of ligand targeted siRNA delivery at Arrowhead. These experiences have facilitated development of Arrowhead’s TRiM (Targeted RNAi Molecule) platform which now serves as the foundation for Arrowhead’s drug development efforts and has been used to develop two new investigational agents, ARO-HBV and ARO-AAT which will enter clinical studies this year.

4:15 Expanding the Chemical Diversity of Therapeutic Oligonucleotides

Maire_OsbornMaire Osborn, PhD, Research Scientist, Khvorova Lab, RNA Therapeutics Institute, University of Massachusetts Medical School

Lipid conjugation markedly enhances the biodistribution, efficacy, duration of effect, and safety of chemically modified siRNAs, both in the central nervous system and systemically. Direct conjugation of a fully chemically modified siRNA to docosahexaenoic acid (DHA), the most abundant polyunsaturated fatty acid in the brain, results in sustained neuronal mRNA silencing in the striatum and cortex after a single injection. When administered systemically, lipid-conjugated siRNAs elicit potent mRNA silencing in liver, kidney, ovary, and adrenal gland, with no increase in systemic toxicological markers. Mechanistically, we show that lipid conjugation drives spontaneous siRNA partitioning into defined classes of circulating plasma lipoproteins in vivo, which increases half-life and promotes oligonucleotide uptake in lipoprotein receptor-expressing cells. Our results establish that hydrophobic modifications can be leveraged to target siRNAs to endogenous lipid transport pathways without the need for synthetic formulation.

4:45 Targeted Augmentation of Nuclear Gene Output

Charles_AllersonCharles R. Allerson, Ph.D., Vice President, Chemistry, Stoke Therapeutics

Most human genetic diseases are due to loss or reduction of function of a single gene, and currently approved therapeutic strategies are unable to directly increase protein expression to treat most of these inherited deficiencies. Stoke Therapeutics is developing first-in-class medicines to treat such monogenic diseases by leveraging antisense oligonucleotides to exploit naturally-occurring reservoirs of non-productive, untranslated pre-mRNA species to increase target protein expression without relying on viral or nanoparticle delivered technologies.

5:15-6:30 Welcome Reception in the Exhibit Hall with Poster Viewing

6:15 End of Day

Tuesday, March 27

7:30 am Breakfast Breakout Roundtable Discussions

Grab a cup of coffee and join a roundtable discussion. These are moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future collaborations around a focused topic.

Delivery Mechanisms for Oligonucleotide Therapeutics

Moderator: Art Levin, Ph.D., Executive Vice President, Research and Development, Avidity Biosciences

  • • Driving forward more effective targeted delivery of oligonucleotide drugs
  • Topical delivery
  • Lipid-enabled delivery
  • Polypeptide-based delivery technology

Chemical Modifications of Oligonucleotide Therapeutics

Moderator: Muthiah (Mano) Manoharan, PhD, Senior Vice President, Drug Discovery, Alnylam Pharmaceuticals, Inc

  • Novel chemical modifications
  • Improving delivery
  • Conjugation

Oligonucleotide Synthesis

Moderator: Nanna Albaek, PhD, Principal Scientist and Group Leader of New Chemistry, Roche Pharma Research and Early Development, Roche Innovation Center Copenhagen

  • Solid phase oligonucleotide synthesis is an established technology. Over the years tremendous improvements have been made, but there is still areas to improve. Which elements of the process would be most beneficial to focus on?
  • Oligonucleotide based therapies are constantly developed and this is to a great extend based on new and more advance chemical modifications. These new building blocks will often require customized synthesis methodologies. How are these best handled and what are the challenges e.g. when oligonucleotides with mixture of chemical modifications are synthesised?
  • Conjugates are becoming more and more important in RNA therapeutics. What are the challenges we face with the introduction of new conjugate moieties, in this regard consider "in solid phase synthesis" conjugation and "post solid phase synthetic" conjugation.


8:25 Chairperson’s Remarks

 Michel Janicot, PhD, CDO, InteRNA Technologies BV

8:30 Development of Novel miRNA Therapeutics to Eliminate Resistant Cancer Stem Cells

Jingfang Ju, PhD, Professor, Pathology, Department of Pathology, Stony Brook University

Resistance to 5-FU based chemotherapy is the major reason for failure of treating patients with advanced colorectal cancer. Novel therapeutics are needed to overcome the challenge of resistance as well as recurrence. We have developed a novel modified miR-129 mimic with enhanced therapeutic potential. The miRNA mimic is more potent at inhibiting cell proliferation and inducing cell cycle arrest at G1 phase than native miRNA while retaining target specificity. It completely prevents colon cancer metastasis in vivo without toxicity. The miRNA mimic can also be delivered to cancer cells without any transfection reagents (e.g. lipids, viral vector, nanoparticles). This represents a significant advancement in the development of a nontoxic and highly potent miRNA based cancer therapeutics.

9:00 miR-195 Potentiates the Efficacy of Microtubule Targeting Agents in Non-Small Cell Lung Cancer

Xiaojie Yu, PhD, Postdoctoral fellow, Greehey Children's Cancer Research Institute, University of Texas Health San Antonio

We report the identification of miR-195 as a sensitizer to microtubule-targeting agents in NSCLC, mediated by its repression of CHEK1. Mouse xenografts with induced or constitutive over-expression of miR-195 show that tumors with high miR-195 expression are more sensitive to drug treatment and that induction of miR-195 potentiates the efficacy of eribulin in repressing tumor growth. These results highlight the possible application of miR-195 expression as a biomarker to predict patient response to MTAs and the potential for delivery of miR-195 mimic as an adjuvant to chemotherapy.

9:30 INT-1B3 – a Chemically-Modified microRNA Mimic Targeting Multiple Hallmarks of Cancer and Representing Potential New Approach to Immunotherapy

Michel Janicot, PhD, CDO, InteRNA Technologies BV

To explore miRNAs as therapeutic agents for the treatment of cancer, InteRNA Technologies has performed functional screens in cell lines covering different types of cancer. Lead candidates are now advancing in preclinical development programs with a focus on hepatocellular cancer. This presentation will provide insights into the latest progress in the preclinical development of InteRNA’s lead miRNA compounds.

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


10:30 Chairperson’s Remarks

 Michel Janicot, PhD, CDO, InteRNA Technologies BV

10:35 RNA Aptamer Delivery Through Intact Skin

Caitlin_Vestal_TibbettsCaitlin Vestal Tibbetts, Team Leader, Aptamer Discovery, GlaxoSmithKline

This study demonstrates that in contrast to expectations, a very-large-molecular-weight RNA based aptamer capable of binding to endogenous IL-23 can permeate across the intact human skin barrier to therapeutically relevant levels into both the epidermis and dermis. The aptamer, highly specific to the human IL-23 cytokine has demonstrated penetration in to intact human skin via fluorescence detection, is at quantifiable levels above the cellular IC50, and remained biologically intact as confirmed by a dual hybridization assay (DHA) and oligo precipitation assay respectively. Target engagement was confirmed by measuring the decrease in IL-17f and IL-22 with topical application of the aptamer but did not show significant changes to IL-23 mRNA levels. This study demonstrates the potential for topically delivering aptamers as therapeutics.

11:05 ZATA’s Novel Oligonucleotides (ZONs) with Self-Neutralizing Backbones

David_TabatadzeDavid Tabatadze, PhD, President and CEO, R&D, ZATA

We developed a nucleic acid platform enabling the new generation oligonucleotides (ZONs) comprising target number of branched charge-neutralizing groups (CNGs) on the internucleoside phosphates of ON by phosphotriester bonds. The CNGs are terminated with positively charged amino groups, and are optimized to form ion pairs with the neighboring phosphate groups. ZONs can be synthesized by standard automated phosphoramidite chemistry in good yield and purity.

11:35 Networking Luncheon

12:30 Dessert Break in the Exhibit Hall with Poster Viewing



1:15 Chairperson’s Remarks

Torsten Hoffmann, PhD, COO, Silence Therapeutics

1:20 Development of Novel Therapies Using Advanced GalNAc-siRNA Technology

Marie Lindholm, PhD, Head of Technology Innovation, Silence Therapeutics

Silence Therapeutics utilizes RNA interference (RNAi) technology to develop a new generation of drugs to treat serious human diseases with unmet needs. Attachment of the N-acetylgalactosamine (GalNAc) moieties to the RNAi triggers (siRNA) allows the resulting conjugates to travel to the liver and to downregulate genes specifically in hepatocytes. We will present our advances with the GalNAc-siRNA technology, as well progress with company’s therapeutic programs.

1:50 Oligonucleotide Therapeutics – Now on Target. Using mAb-directed Delivery and Uptake to Modulate Gene Expression

Art_Levin Art Levin, Ph.D., Executive Vice President, Research and Development, Avidity Biosciences

Delivery remains a key limitation to the use of oligonucleotide-based therapeutics. Uptake of oligonucleotides is limited by their high molecular weights and hydrophilicity, independent of whether the oligonucleotide works through siRNA, antisense or splice switching mechanisms. It is now known that siRNA and antisense molecules conjugated to GalNAc bind to and are internalized by the asialoglycoprotein receptor on hepatocytes, and recent data demonstrate receptor-mediated uptake increases the efficacy of the GalNAc-conjugated oligonucleotides up to 30-fold. Although there are multiple diseases of hepatocellular origin, effective delivery of oligonucleotides to a larger repertoire of cell types would enable oligonucleotide technologies to be applied more broadly and effectively across a range of diseases. We have generated antibody-oligonucleotide conjugates with double stranded and single stranded payloads that deliver oligonucleotide payloads in multiple tissues and cell types. Applications of the technology in various disease indications will be discussed.

2:20 LUNAR™: A Novel, Potent, Safe and Versatile Nucleic Acid Delivery Platform

Priya_KarmaliPriya P. Karmali, PhD, Senior Director, Pharmaceutical Development, Arcturus Therapeutics

Arcturus has developed a novel, potent and safe delivery platform called LUNAR™, a proprietary lipid-enabled delivery system for nucleic acid medicines. Versatility of LUNAR™ platform enables effective delivery of a wide range of nucleic acids including mRNA, siRNA, miRNA, antisense and DNA to the liver, lung and other target tissues. This presentation will provide an update on advancements made for LUNAR™ platform in terms of its potency improvements, manufacturability, scalability and in vivo proof of concept achieved for multiple RNA medicine programs.

2:50 Refreshment Break in the Exhibit Hall with Poster Viewing


3:35 GalXC RNAi Technology: Towards Functional Cure of Chronic Hepatitis B Infection

Marc_AbramsMarc Abrams, PhD, Senior Director, Preclinical Development, Dicerna Pharmaceuticals, Inc.

GalXC technology represents a novel structural class of subcutaneously-administered, hepatocyte-targeting RNAi therapeutics which can silence any expressed RNA with high specificity and long duration. Chronic Hepatitis B Virus (HBV) infection is a significant cause of worldwide morbidity and mortality. We will report data from multiple preclinical models and discuss a novel mechanism which differentiates GalXC-HBVS from other oligonucleotide-based approaches.

4:05 Therapeutic Protein Expression in vivo Using Messenger RNA-Lipid Nanoparticles

Thomas_MaddenThomas D. Madden, PhD, President and CEO, Acuitas Therapeutics

Therapeutic applications of messenger RNA (mRNA) are currently being advanced into clinical development. However, mRNA is relatively labile and requires a delivery system to efficiently access the cytoplasmic compartment where the mRNA is translated. Acuitas is developing lipid nanoparticle systems (LNP) that allow the efficient delivery and expression of mRNA via different routes of administration. Biophysical characteristics that facilitate efficient mRNA delivery and provide a favorable safety profile will be discussed.

4:35 Development of Anti-Fibrosis siRNA Therapeutics Using HKP Polypeptide Nanoparticle Technology

Patrick_LuPatrick Y. Lu, PhD, President & CSO, Sirnaomics, Inc.

Using a proprietary and optimized polypeptide-based delivery technology, we have developed the novel anti-fibrotic therapeutics with siRNAs targeting both TGFß1 and Cox-2 simultaneously, for initial indication of skin hypertrophic scar followed with liver fibrosis and other fibrotic conditions. I will discuss the unique advantage of HKP polypeptide nanoparticle technology for efficient siRNA delivery, its pharmaceutical properties for manufacturing and its preclinical safety profile.

5:05 Delivery of RNAi and Oligonucleotide Therapeutics and Diagnostics via Self-Assembled Nanopieces

Qian_ChenQian Chen, PhD, Professor, Medical Science, Brown University; Chair, SAB, NanoDe Therapeutics Inc.

There is a great need for RNA delivery technology for non-liver and hard-to-deliver tissues. We developed NanopiecesTM (NPs), a novel platform delivery technology to penetrate dense tissues and deliver RNAi intracellularly in a non-toxic manner. NPs disassemble within target cells spontaneously, releasing RNAi therapeutics to modify diseases including bone tumors, post-traumatic joint injuries, and rheumatoid arthritis in animal models. NPs can also achieve in vivo mRNA diagnostics by delivering molecular beacons to live animals for monitoring pro-inflammatory gene expression in real time.

5:05 Dinner Short Course Registration

5:30-8:30 SC3: CRISPR-Based Gene Editing for Targeted Therapies*

While the challenges and risks associated with oligonucleotide therapies still remain, there is a new and better understanding of how genes can be effectively manipulated and delivered. With the rise of gene editing tools and enhanced knowledge of targeted delivery, these therapeutic modalities are once again being embraced with renewed hope and enthusiasm. This course helps you understand how gene editing – particularly the one enabled by the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas9 system – works, and how it can be used to help develop targeted therapies with good efficacy and delivery.


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

Ciro Bonetti, PhD, Scientist, Regeneron Pharmaceuticals

Eric B. Kmiec, PhD, Director, Gene Editing Institute; Senior Research Scientist, Center for Translational Cancer Research, Helen F. Graham Cancer Center & Research Institute, Christiana Care Health System

* Separate registration required.

Wednesday, March 28

8:00 am Morning Coffee


8:25 Chairperson’s Remarks

Art Krieg, MD, Founder and CEO, Checkmate Pharmaceuticals

8:30 Making “Cold” Tumors “Hot” with Intratumoral Injection of CpG-A Oligonucleotide

Art_KriegArt Krieg, MD, Founder and CEO, Checkmate Pharmaceuticals

CMP-001 is a formulation of a CpG-A oligonucleotide, G10, within a virus-like particle, Qb. We are performing a Phase Ib dose escalation study of intratumoral CMP-001 given in combination with systemic pembrolizumab in advanced melanoma patients whose cancer has previously progressed on an anti-PD-1 Ab, or who have failed to respond to at least 12 weeks of such therapy.

9:00 TLR9-Targeted Spherical Nucleic Acids for Cancer Immunotherapy

Ekambar_KandimallaEkambar Kandimalla, PhD, CSO, R&D, Exicure

Spherical nucleic acids (SNAs) are dense and radially arranged synthetic oligonucleotides on a central nanoparticle core. The 3D structure of SNA provides enhanced cellular uptake, and nuclease stability, compared with linear oligonucleotides with advantages for local delivery. A novel TLR9-targeted SNA has shown greater antitumor activity as a monotherapy and in combination with an anti-PD-1 antibody compared with a linear oligo in syngeneic tumor models with the induction of innate immune responses and long-term tumor-specific memory responses to subsequent challenge with the same tumor cell line.

9:30 Bi-Functional CpG-STAT3 Antisense Oligonucleotides for Immunotherapy of Metastatic Prostate Cancer

Marcin_KortylewskiMarcin Kortylewski, PhD, Associate Professor, Department of Immuno-Oncology, City of Hope

Here, we describe a bi-functional oligonucleotide with immunogenic and tolerance-breaking activities, which overcome STAT3-dependent resistance of prostate cancers to immunotherapy. STAT3 antisense oligonucleotide (ASO) tethered to immunogenic CpG-A oligonucleotide showed improved, compared to STAT3ASO alone, biodistribution into the bone marrow and potency of STAT3 knockdown after systemic administration. Treatment with CpG-STAT3ASO conjugate, but not CpG or STAT3ASO alone, led to regression of bone-localized prostate cancers in mice through potnent immune-mediated effects, with the increased tumor infiltration by CD8+ T cells and reduced percentage of regulatory T cells and PD-L1+ MDSCs.

10:00 Networking Coffee Break



10:30 RNAi-Based β-Catenin Inhibition Results in Regression of Highly Immunosuppressive Wnt-Activated Tumors in Combination with IDOi/PD-1 Immunotherapy

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

DCR-BCAT is an RNAi-based experimental drug targeting β-catenin, formulated in a tumor-selective nanoparticle. Wnt/β-catenin signaling has been implicated as a mechanism of resistance to cancer immunotherapy. In preclinical models, systemic administration of DCR-BCAT induced rapid increases in tumor T-cells and dramatically improved responses to immunotherapy agents. Additionally, Wnt signaling promotes constitutive IDO1 expression in some tumor contexts, which in turn promotes recruitment and expansion of immunosuppressive cell types to the tumor microenvironment. DCR-BCAT counteracts immunosuppression by T-cell recruitment and causes regression, when co-administered with anti-PD(L)-1 and IDO1 inhibitors.

11:00 SB 11285, a Novel STING Agonist for Immunotherapy of Cancer

Kris_IyerR.P. (Kris) Iyer, PhD, Co-Founder & CSO, Spring Bank Pharmaceuticals

Immunotherapy has emerged as a transformative approach for the treatment of cancer. Evidence suggests that the activation of Stimulator of Interferon Genes (STING) pathway in tumor cells and/or immune cells induce type I Interferon production leading to apoptosis of tumor cells, as well as induction of adaptive immune response, thereby providing a powerful anti-cancer strategy. Herein, we describe the discovery and preclinical studies of SB 11285, a novel STING agonist for application in immuno-oncology.

11:30 Opportunities for Antisense Oligonucleotides in Cancer Immunotherapy

Frank_JaschinskiFrank Jaschinski, PhD, CSO, Secarna Pharmaceuticals

Immunotherapy has emerged as a promising approach for treatment of cancer. Secarna is targeting immunosuppressive factors within the tumor microenvironment using 3rd generation antisense oligonucleotides. Preclinical data will be presented that show the progress of Secarna’s program targeting immunosuppressive factors such as the ectonucleotidases CD39 and CD73.

12:00 Enjoy Lunch on Your Own

Exploring Innovative Strategies

1:15 Chairperson’s Remarks

James J. HickmanJames J. Hickman, PhD, Founding Director, NanoScience Technology Center; Professor, Nanoscience Technology, Chemistry, Biomolecular Science, Material Science and Electrical Engineering, University of Central Florida

1:20 From Rare to Common: Targeting Gaucher Defects for the Treatment of Parkinson’s Disease

S. Pablo Sardi, PharmD, PhD, R&D Director, Sanofi Genzyme

Clinical, genetic and experimental evidence underlies the relevance of lysosomal dysfunction in Parkinson’s disease. Stimulation of the lysosomal GBA pathway in the CNS can improve the pathological and behavioral abnormalities in animal models of disease. Modulation of this lysosomal pathway may represent a new disease-modifying treatment for GBA-related Parkinson’s disease. This research underscores the study of rare diseases as a new paradigm for drug discovery.

1:50 Orphan Indications as a Step to Developing Therapeutics for Major Unmet Medical Needs

Elena FeinsteinElena Feinstein, MD, PhD, CSO, Quark Pharmaceuticals

This talk will present Quark’s strategy of drug development from proof-of-concept in orphan indications to major ones with similar underlying pathogenesis. A case study of development of QPI-1002, an siRNA targeting p53, from an orphan indication such as delayed graft function following kidney transplantation towards acute kidney injury following cardiac surgery will be discussed.

2:20 Preclinical Development of a CRISPR Medicine for the Treatment of Leber Congenital Amaurosis Type 10

Gerry CoxGerry Cox, MD, CMO, Editas Medicine

A common mutation in intron 26 of the CEP290 gene, c.2991+1655A>G, leads to retinal degeneration and infantile-onset blindness known as Leber congenital amaurosis type 10 (LCA10). A therapeutic approach involving subretinal delivery of AAV5 encoding CRISPR components is being developed to remove the mutation and potentially restore vision. Opportunities and preclinical challenges of developing human genome-based medicines for LCA10 will be discussed.

2:50 Efficient Delivery and Nuclear Uptake for Gene Editing in CD34+ Cells Directed by a CRISPR/Cas9 Ribonucleoprotein Complex

Eric. B. KmiecEric. B. Kmiec, PhD, Director, Gene Editing Institute; Senior Research Scientist, Center for Translational Cancer Research, Helen F. Graham Cancer Center & Research Institute, Christiana Care Health System

Successful editing of the beta globin gene in CD34+ cells is a milestone for ex vivo cell therapy. While dramatic advances have been reported in the literature, by and large, the experimental protocols and conditions have been less than robust. We began a systematic evaluation of the relationship among cellular delivery, nuclear uptake and gene editing activity and defined the critical parameters for CRISPR/Cas9 RNP and ssODNs delivery into CD34+ cells.

3:20 Networking Refreshment Break

3:35 Developing a First-in-Class Drug for Familial Amyloid Polyneuropathy: A Case Study

Christine Bulawa, PhD, Senior Director, Rare Disease Research Unit, Pfizer

This talk will present a case study of drug development for familial amyloid polyneuropathy (FAP), a disease caused by mutations in the circulating protein transthyretin. Insights gleaned from biophysical studies of transthyretin and clinical observations of FAP patients led to the therapeutic strategy of native state stabilization and ultimately to development of tafamidis, the first disease modifying therapy for an amyloid disease.

4:05 Human-on-a-Chip Systems Applied to Rare Disease Investigations for Efficacy and Toxicity

James J. HickmanJames J. Hickman, PhD, Founding Director, NanoScience Technology Center; Professor, Nanoscience Technology, Chemistry, Biomolecular Science, Material Science and Electrical Engineering, University of Central Florida

Our focus is on establishing functional in vitro systems where we seek to create organs and subsystems to model motor control, muscle function, myelination and cognitive function, as well as cardiac and hepatocyte subsystems for neurodegenerative diseases such as ALS as well as other rare diseases. Functional 2 and 4-organ systems where multi-organ toxicity as well as efficacy are evaluated will be discussed.

4:35 Case Study: Identification and Development of SLN124, a Conjugated GalNAc-siRNA Therapeutic for the Treatment of Iron Overload Disorders 

Torsten Hoffmann

Torsten Hoffmann, PhD, COO, Silence Therapeutics

Conjugation of the N-acetylgalactosamine (GalNAc) moieties to siRNAs allows precise and highly effective knockdown of various genes in the liver, specifically in hepatocytes, of the vertebrate organisms. We will describe how Silence Therapeutics develops novel therapeutic programs addressing hepatocyte-associated diseases using its proprietary GalNAc-siRNA technology. In this case study, the discovery of SLN124 will be described in greater detail.


 5:05 Close of Conference

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