Final weeks to register!
Oligonucleotide–based therapeutics have long formed the third major drug development platform, specifically focused on modulating gene expression by targeting RNA or the genome itself. A key distinguishing attribute of nucleic acids as therapeutic agents is their ability to access the “undruggable” space left by small molecules and biologics, allowing drug developers to address a wider range of diseases, and particularly those with limited or no therapeutic options. This has generated significant interest in this field; however, first generation molecules exhibiting potency and safety issues have hindered the potential of oligonucleotide therapies dramatically impacting the drug development landscape. Recent advances in nucleic acid chemistry and delivery to improve stability, bioavailability, specificity and potency are now driving the rapid development and clinical evaluation of a new generation of therapies poised for success.
The Oligonucleotide Therapeutics and Delivery conference, April 4-5, in Cambridge, MA will gather leading drug developers and discovery scientists to discuss technological and scientific advances in oligonucleotide-based therapeutics.
Sunday, April 3rd | 5:00 – 8:00 pm
SC1: Oligonucleotide Therapeutics: From Discovery to Manufacturing
RNAi/antisense oligonucleotides can target virtually any disease causing gene and promise to become a third major class of therapeutics (besides small molecules and biologics). For this to happen, however, several challenges have to be addressed. This workshop will discuss considerations taken into account, when selecting oligonucleotide therapeutic programs: from target and delivery selection to developmental and manufacturing particularities.
Detailed discussion will focus on, but not limited to, the tightly interconnected factors of therapeutic indication, delivery and targets, as well as chemistry manufacturing and controls (CMC), regulatory, cost, and intellectual property considerations. Developers who are seeking a comprehensive and up-to-date overview from recognized oligonucleotide development experts are highly encouraged to join.
Instructors:
- Dmitry Samarsky, Ph.D., Senior Vice President, Technology & Global Business Development, OliX Pharmaceuticals,
- Muthiah (Mano) Manoharan, Ph.D., Senior Vice President, Drug Discovery, Alnylam Pharmaceuticals, Inc.
- Punit Seth, Ph.D., Executive Director, Medicinal Chemistry, Ionis Pharmaceuticals (formerly Isis Pharmaceuticals)
- Alexey Wolfson, Ph.D., Founder and CSO, MirImmune; CEO, Advirna
- Konstantin M. Linnik, Ph.D., Partner, Intellectual Property, Nutter, McClennen & Fish, LLP; former Lead Patent Counsel for Oligonucleotide Therapeutics at Pfizer, Inc.
- Ryszard Kole, Ph.D., Distinguished Scientist, Sarepta Therapeutics
*Separate registration required - dinner will be provided.
Day 1
Monday, April 4th
7:00am Registration and Morning Coffee
8:10 Chairperson’s Opening Remarks
Dmitry Samarsky, Ph.D., Senior Vice President, Technology & Global Business Development, OliX Pharmaceuticals, Inc.
8:15 Keynote Presentation: GalNAc-Conjugated siRNAs as a New Paradigm in Oligonucleotide Therapeutics
Muthiah (Mano) Manoharan, Ph.D., 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 Development of Stereopure Nucleic Acid Therapeutics
Chandra Vargeese, Ph.D., 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.
9:15 Novel Phosphorodiamidate Oligomers (PMOs) for the Treatment of Genetic and Infectious Diseases
Bruce Wentworth, Ph.D., Vice President, Biology, Sarepta Therapeutics
PMOs are being tested in advanced clinical trials for the treatment of patients with Duchenne muscular dystrophy (DMD), a rare, X-linked disease that results in progressive muscle loss and premature death. Research has shown that for other disorders, including viral and bacterial infection as well as rare diseases such as Pompe disease, modified PMOs may be more appropriate due to their potential for enhanced delivery and tissue targeting. The PMO-based technology has the potential to be a versatile, modifiable, and widely applicable treatment in any number of disease states.
9:45 Selected Presentation: Steric Hindrance Antisense Oligonucleotide (AON)-Based Targeting of MDM4 Exon6 in Cancer Therapy
Ernesto Guccione, Ph.D., Principal Investigator, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)
MDM4 is a promising target for cancer therapy. Whereas MDM4 protein is undetectable in most normal adult tissues, cancer cells often up-regulate its expression to dampen p53 tumor suppressor function. The molecular mechanisms underlying this up-regulation are largely unknown. We show herein that this key oncogenic event largely depends on a specific alternative splicing switch. While a nonsense-mediated decay isoform of MDM4 (MDM4-S) is produced in normal adult tissues as a result of exon 6 skipping, enhanced exon 6 inclusion leads to MDM4 full length protein expression in a large number of human cancers. Although this alternative splicing event is likely regulated by multiple splicing factors, we identified the SRSF3 oncoprotein as a key enhancer of exon 6 inclusion. Importantly, steric Hindrance Antisense Oligonucleotide (shAON)-mediated skipping of exon 6 decreases MDM4 protein abundance, the growth of melanomas and enhances their sensitivity to MAPK-targeting therapeutics both in vitro and in melanoma patient-derived xenograft mouse models. In addition, we provide proof-of-concept evidence that MDM4-targeting AON-based therapy is applicable to a wide range of tumor types. We conclude that enhanced MDM4 exon 6 inclusion is a common oncogenic event and a clinically-compatible therapeutic target.
10:15 Coffee Break in the Exhibit Hall with Poster Viewing
10:45 Featured Presentation: Structure Activity Relationships of Trivalent GalNAc Conjugated Antisense Oligonucleotides
Punit Seth, Ph.D., Executive Director, Medicinal Chemistry, Ionis Pharmaceuticals (formerly Isis Pharmaceuticals)
Trivalent GalNAc, a high affinity ligand for the hepatocyte-specific Asialoglycoprotein receptor (ASGR), enhances the potency of antisense oligonucleotides (ASOs) for inhibiting gene targets expressed in hepatocytes. We undertook a comprehensive structure-activity relationship study to determine the optimal structural requirements for enhancing ASO potency via ASGR mediated delivery to hepatocytes. As part of this effort, GalNAc clusters assembled from six distinct branched or amino acid scaffolds were synthesized and attached to ASOs using simplified solution-phase or phosphoramidite based methods. Within each cluster, the length and hydrophobicity of the linker attaching the GalNAc sugar to the branching point on the scaffold was varied. The effect of reducing backbone phosphorothioate content (PS) and changing the linker moiety between the GalNAc cluster and the ASO was also evaluated. Details from this work which resulted in the selection of a simplified trivalent GalNAc ASO conjugate for evaluation in human trials will be presented.
11:15 Phosphorodithioate RNA for RNA-Based Therapeutics
Xianbin Yang, Ph.D., Director, R&D, AM Biotechnologies
During this presentation I will discuss the chemistry for synthesizing phosphorodithioate (PS2)-modified siRNAs, aptamer, and anti-miRNAs; crystal structures of PS2-modified siRNAs and protein-RNA complexes; therapeutic aptamers with remarkably improved binding affinity (from nM to pM) with a single PS2 substitution; and in vitro and in vivo gene silencing activity of PS2-substituted RNA.
11:45 CASE STUDY: Reversing the Effect of Oncogenic hTERT Promoter Mutations with Strand-Invading Oligonucleotides
Donald M. Miller, M.D., Ph.D., Professor of Medicine and Pharmacology; Chief, Division of Medical Oncology and Hematology; Director, James Graham Brown Cancer Center; University of Louisville School of Medicine
More than 80% of melanomas and glioblastomas have mutations in the hTERT promoter. We have shown that these mutations destabilize the promoter quadruplex structure and allow increased hTERT expression and cellular proliferation. Mutation-targeted G-rich oligonucleotides bind to the mutated C-rich strand, stabilizing the quadruplex structure in the "off" position. In cells containing the mutated promoter sequence, these oligonucleotides inhibit hTERT expression and cellular proliferation, resulting in apoptosis. We will discuss the potential therapeutic utility of these strand-invading oligonucleotides.
12:15 Lunch On Your Own
1:25 Chairperson’s Remarks
Art Krieg, M.D., Founder and CEO, Checkmate Pharma
1:30 Featured Presentation: Prospects for Increasing the Response Rates to Checkpoint Inhibition: The Role of TLR9
Art Krieg, M.D., Founder and CEO, Checkmate Pharma
Many immunologists have speculated that combining a strong Th1 immune activator known to be capable of inducing multifunctional anti-tumor CD8+ T cell responses in cancer patients together with anti-PD-1/PD-L1 would greatly increase the response rates to therapy compared to either agent alone. Checkmate’s TLR9 agonist program has shown such a response in humans with excellent safety, and will be moving into clinical development in combination with an anti-PD-1 antibody in advanced cancer patients in early 2016.
2:00 Cell-Based Cancer Immunotherapy in Suppressive Environment: Immune Checkpoint Knockdown by Self-Deliverable RNAi
Alexey Wolfson, Ph.D., Founder and CSO, MirImmune; CEO, Advirna
MirImmune uses a proprietary RNAi-based technology to knockdown immune checkpoints in therapeutic cells to protect them from immunosuppression and improve their tumor-killing properties. We present results demonstrating the use of self-deliverable RNAi to suppress gene expression in T-cell and the effect of immune checkpoint knockdown on T-cells properties in vitro and in vivo. Improvements of T-cell efficacy by PD-1 knockdown will be demonstrated in two different systems: (i) tumor-infiltrating lymphocytes (TIL) for melanoma treatment and (ii) mesothelin-targeting CAR-T cells for the treatment of ovarian cancer.
2:30 CureVac’s Sequence-Optimized mRNA – En Route to the Next Generation Biologicals
Mariola Fotin-Mleczek, Ph.D., CSO, CureVac
Recent advances strongly suggest that mRNA is the basis for a new class of vaccines and drugs. RNActive®, one of CureVac’s technologies has been developed on this basis and provides potent prophylactic vaccines and novel immunotherapies against cancer. These successes could be extended preclinically to mRNA protein and gene replacement therapy. The production of mRNA-based vaccines and drugs is highly flexible, scalable and cost competitive, and eliminates the requirement of a cold chain. Furthermore CureVac’s proprietary optimization process allows the generation of sequence optimized yet natural mRNA that provides a safe and efficient method for enabling the human body to produce its own medicine.
3:00 Refreshment Break in the Exhibit Hall with Poster Viewing
3:30 Oligonucleotide Aptamer Targeted RNA Therapeutics: A Novel Platform for Cancer Immunotherapy
Eli Gilboa, Ph.D., J. Enola Dodson Professor, Microbiology & Immunology, UM/Sylvester Comprehensive Cancer Center; Director, Dodson Interdisciplinary Immunotherapy Institute, Leonard Miller School of Medicine, University of Miami
Immune therapy is emerging as a promising modality to treat cancer. Successful control of tumor progression will require the development of multi-pronged and clinically feasible approaches that will also address the dose limiting toxicities of immune modulatory drugs. In this presentation I will describe the use of complementary and synergistic strategies to potentiate antitumor immunity in cancer patients using oligonucleotide aptamer platforms to target immune modulatory siRNAs or aptamers to the immune system or the tumor microenvironment, respectively. Aptamer targeted delivery of RNA therapeutics reduces the toxicities associated with their systemic administration, and the cell-free chemically synthesized nature of the oligonucleotides enhances their clinical applicability.
4:00 Immunomodulatory Spherical Nucleic Acids
David Giljohann, Ph.D., CEO, Exicure
Immunomodulatory nucleic acids act by agonizing or antagonizing endosomal toll-like receptors (TLR3, TLR7/8, and TLR9), proteins involved in innate immune signaling. Immunomodulatory spherical nucleic acids (SNAs) that stimulate (immunostimulatory, IS-SNA) or regulate (immunoregulatory, IR-SNA) immunity by engaging TLRs have been designed, synthesized, and characterized. IR-SNAs exhibit up to eightfold increases in potency and 30% greater reduction in fibrosis score in mice with nonalcoholic steatohepatitis (NASH). Given the clinical potential of SNAs due to their potency, defined chemical nature, and good tolerability, SNAs are attractive new modalities for developing immunotherapies.
4:30 Cancer Immunotherapy: Charting a Course in the Rough Seas of Intellectual Property
Konstantin M. Linnik, Ph.D., Partner, Intellectual Property, Nutter, McClennen & Fish, LLP; former Lead Patent Counsel for Oligonucleotide Therapeutics at Pfizer, Inc.
Both immuno-oncology and oligonucleotide IP spaces are crowded – the number of drugs in R&D far exceeds the number of targets. Navigating the IP around major targets is critical but, more importantly, every drug developer faces challenges in protecting its own intellectual property. What are the patenting strategies that allow entry into this crowded IP space, while preserving the broadest scope of protection and commercialization opportunities?
5:00 Welcome Reception in the Exhibit Hall with Poster Viewing
6:00 End of Day
Day 2
Tuesday, April 5th
7:30am Roundtable Discussions with Continental Breakfast
8:25 Chairperson’s Remarks
Andrew Vaillant, Ph.D., CSO, Replicor Inc.
8:30 Nucleic Acid Polymers: Antiviral Mechanisms and Application in the Treatment of Chronic HBV and HBV / HDV Infection
Andrew Vaillant, Ph.D., CSO, Replicor Inc.
Nucleic acid polymers (NAPs) are a newly emerging antiviral technology for the treatment of chronic HBV infection and HBV / HDV co-infection. NAPs have the unique ability to clear HBsAg from the blood of human patients, a critical step in achieving a functional cure in HBV and HBV / HDV infection. Replicor will present its current mechanistic data underlying the basis for this unique antiviral effect of NAPs as well as updated clinical data showing Replicor’s progress in using NAP-based combination therapy in patients with chronic HBV infection and HBV / HDV co-infection towards achieving functional cure for these infections.
9:00 CMX157, a Novel, Liver-Targeted, Tenofovir Prodrug, for the Treatment of Chronic HBV Infection
John Sullivan-Bólyai, M.D., CMO, ContraVir Pharmaceuticals, Inc.
CMX157 is a novel, liver-targeted, lipid conjugate prodrug of tenofovir (TFV) designed to utilize natural lipid uptake pathways to achieve high hepatocellular levels of the active antiviral. Greater than 60 fold potency vs. TFV, high plasma stability and high first-pass liver extraction are expected to result in low clinical doses, anchoring single pill antiviral combinations, decreasing circulating TFV and off-target TFV toxicities, particularly to bone and kidneys, compared to the currently licensed TFV prodrug.
9:30 Lipid-Crystal Nano-Particles: Formulation and Delivery of Oligonucleotides
Raphael Mannino, Ph.D., CTO, Matinas BioPharma, Inc.
Cochleates are lipid crystals formed upon the interaction of charged lipids and cations. Drugs and oligonucleotides can be formulated so that they become sequestered within the layers of this stable structure. Once cochleates are inside a cell and exposed to low calcium ion concentrations they open and release their contents.
9:45 Coffee Break in the Exhibit Hall with Poster Viewing
10:25 Chairperson’s Remarks
Balkrishen (Bal) Bhat, Ph.D., Vice President, Chemistry, RaNA Therapeutics
10:30 Novel Strategies for Endogenous mRNA Upregulation
Balkrishen (Bal) Bhat, Ph.D., Vice President, Chemistry, RaNA Therapeutics
Gene up-regulation is becoming one of the most important disease treatment paradigms. RaNA is developing two novel approaches for endogenous mRNA upregulation. In first approach the recruitment of polycomb repressive complex (PRC2) to long non coding RNA (lncRNA) is blocked by short single stranded oligonucleotides. These oligonucleotides are designed to bind to the identified loci of long non coding RNA via Watson-Crick hydrogen bonding. We demonstrate that by blocking the interaction of PRC2 and lncRNA at the SMN2 locus resulted in significant and selective up-regulation of the SMN mRNA and protein. These results provide potential for the treatment of spinal muscular atrophy (SMA) a neurogenerative disease via a novel mechanism. The second approach leverages our understanding and knowledge that increasing the endogenous mRNA half-life would lead to up-regulation of target mRNA and corresponding protein. We demonstrate that chemically modified short single stranded oligonucleotides bind to targeted regions of mRNA and stabilize it against nuclease degradation which results in increased half-life and up-regulation of mRNA and protein. The examples of in vitro and in vivo proof of concept will be presented.
11:00 Development of Novel Breakthrough Cancer Therapies Based on the Unique Functions of miRNAs
Iman Schultz, Ph.D., Project Manager, R&D, 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. A number of miRNAs were selected based on the results from different cell-based assays, and lead candidates are now advancing in pre-clinical development programs for hepatocellular, skin (melanoma), head and neck, pancreatic, bladder and prostate cancer. We have gained a significant understanding of the molecular mechanisms of action of the most promising candidates from extensive in vitro analyses, and their efficacy is currently explored in human cancer xenograft models in the mouse. This presentation will provide insights into the latest progress in the pre-clinical development of InteRNAs lead miRNA compounds.
11:30 Development of Lipid-Based Oligonucleotide Delivery Systems
Volker Fehring, Ph.D., Director, Formulation Development, Silence Therapeutics GmbH
In vivo delivery is still one of the most challenging parts when it comes to the therapeutic application of nucleotides like siRNA and mRNA. Here we discuss how Silence Therapeutics has broadened its portfolio of lipid-based formulations, how lipid chemistry influences specificity and activity, and certain process parameters that led to new formulations characteristics.
12:00pm Luncheon Presentation (Sponsorship Opportunity Available) or Lunch On Your Own
1:00 Chairperson’s Remarks
Dong-ki Lee, Ph.D., Professor, Sungkyunkwan University, South Korea; CEO, OliX Pharmaceuticals
1:05 nOligos: A Cell Specific Oligonucleotide Delivery Platform: Application to MDD and PD Treatments
Andres Montefeltro, Ph.D., CEO, nLife Therapeutics, S.L.
nLife Therapeutics has developed different nucleic acid chemical modifications with the aim to optimize cell specific delivery capabilities to neurons. We have combined siRNAs and antisense oligonucleotides (ASOs) with some specific and potent small molecule ligands to neuronal receptors or transporters, named nOligos (neuronal specific oligonucleotides). These combinations proved to deliver the nucleic acid to the target neuron in an effective way. Also, the intranasal administration of the modified nucleic acids reached the targeted brain area and neurons in mice and monkeys.
1:35 Exosome Mediated Delivery of Therapeutic Oligonucleotides for Treatment of Neurodegenerative Disorders
Anastasia Khvorova, Ph.D., Professor, Molecular Medicine, RNA Therapeutics Institute, University of Massachusetts Medical School
Oligonucleotide therapeutics is a new class of drugs, the clinical utility of which has been limited by inefficient tissue distribution and cellular uptake. Through our research, we have developed a novel methodology that enables the loading of hydrophobically modified oligonucleotides (hsiRNA) into exosomes. These hsiRNAs show efficient cellular uptake in vitro as well as broad brain distribution and in vivo efficacy. Exosome-formulated oligonucleotide therapeutics might be a solution for the development of novel therapeutics for the treatment of neurodegenerative disorders.
2:05 Featured Presentation: Therapeutic Development Using the Second Generation RNAi Triggers
Dong-ki Lee, Ph.D., Professor, Sungkyunkwan University, South Korea; CEO, OliX Pharmaceuticals
Recent studies came up with novel RNAi triggering molecular structures with unique structural features and functional advantages compared with the conventional siRNA. During this presentation I will introduce novel RNAi triggers developed in my laboratory, with improved features over conventional siRNA, such as reduced off-target effects, enhanced cellular delivery when complexed with cationic delivery vehicles, and specific target gene silencing combined with immunostimulation. One of these second generation RNAi triggers, asymmetric siRNAs (asiRNAs), were combined with specific set of chemical modifications to generate cell-penetrating asiRNAs (cp-asiRNAs), which can execute gene silencing without delivery vehicle both in vitro and in vivo. I will introduce current therapeutic development programs based on the cp-asiRNA structures.
2:35 A Novel Nano-Medicine Platform for Oligonucleotide Discovery and Delivery
Art Levin, Ph.D., Executive Vice President, Research and Development, Avidity NanoMedicines
Despite the considerable promise, delivery has proven to be one of the central challenges of oligonucleotide-based therapeutics. Oligonucleotides are large, hydrophilic and highly negatively charged, so they don’t cross cell membranes. We have pioneered the development of Precision NanoMedicines, which are targeted, polymeric nanoparticles encapsulating siRNA drug payloads for delivery to specific tumor types. These self-assembling nanoparticles can be decorated with antibodies, proteins, peptides and small molecules to bind to extracellular receptors and facilitate cellular uptake.
3:05 Refreshment Break in the Exhibit Hall with Poster Viewing
3:45 DsiRNA Applications for Oncology and Chronic Liver Diseases
Marc Abrams, Ph.D., Senior Director, Preclinical Development, Dicerna Pharmaceuticals, Inc.
Dicerna is advancing two platforms for delivery of Dicer-substrate siRNAs (DsiRNA): EnCore lipid nanoparticles for oncology, and GalNAc-DsiRNA-EX conjugates for liver indications. Lipid Nanoparticle (LNP) technology is an elegant solution for delivery of RNAi triggers, since it enables both bioavailability to target organs as well as the ability to transfect target cells. Dicerna’s unique LNP platform delivers DsiRNAs to tumors of diverse origin. An optimized EnCore LNP containing a DsiRNA targeting CTNNB1, the gene encoding β-catenin, demonstrates anti-tumor efficacy in both xenografted tumors and spontaneous genetically-driven tumors. This formulation, DCR-BCAT, also demonstrates synergistic efficacy with other DsiRNAs and with small molecule cancer drugs. For RNAi indications in normal liver, GalNAc-DsiRNA-EX conjugates are a platform that enables high potency, stability and duration for RNAi delivery to hepatocytes. Examples for several targets in rodents and non-human primates will be covered.
4:15 Translation of Messenger RNA Therapeutics from Preclinical Research into Clinical Studies
Pad Chivukula, Ph.D., CSO & COO, Arcturus Therapeutics
Arcturus has developed a novel, potent and safe RNA Therapeutics platform called LUNAR™, a proprietary lipid-enabled delivery system for RNA medicines including small interfering RNA, messenger RNA, antisense and microRNA oligotherapeutics. In addition, we incorporate Unlocked Nucleic Acid (UNA) chemistry into the oligonucleotide drug candidate enabling the targeting of any gene in the human genome. This presentation will provide an update on our lead asset, an UNA-modified, LUNAR-formulated siRNA targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis.
4:45 Clinical Development of RXI-109 to Reduce the Formation of Scars
Pamela Pavco, Ph.D., Chief Development Officer, RXi Pharmaceuticals Corp.
RXI-109 is a self-delivering RNAi compound (sd-rxRNA®) in development as a therapeutic to target and reduce connective tissue growth factor (CTGF) in order to impede the fibrotic pathway. Preliminary results from Phase 2a dermal clinical trials indicate a better outcome (reduced scar formation) following hypertrophic scar revision surgery when the incision site is treated by intradermal injections of RXI-109. A summary of the ongoing dermal trials and an overview of a Phase 1/2 trial to prevent subretinal fibrosis in subjects with neovascular age-related macular degeneration will be discussed.
5:15 Small Molecules that Enhance the Pharmacological Effects of Oligonucleotides
Rudolph L. Juliano, Ph.D., Boshamer Distinguished Professor, Department of Pharmacology, University of North Carolina
Endosomal trapping is a key impediment to the effective use of oligonucleotides in therapy. We have used high throughput screening to identify small molecules that selectively release oligonucleotides from the late endosome compartment thus increasing access to the cytosol and nucleus. These compounds substantially enhance pharmacological effects of several types of oligonucleotides both in cell culture and in mouse models.
5:45 Close of Conference
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