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May 20-23, 2012 -
May 20-23, 2012
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TIDES: Oligonucleotide and Peptide® Research, Technology and Product Development
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Oligonucleotide Therapeutics Discovery
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Oligonucleotide Therapeutics Discovery
Improving Drug-Like Properties to Accelerate Preclinical and Clinical Development
Courses: Sunday | Plenary Sessions: Monday | Main Conference: Tuesday | Wednesday
8:15
Chairperson's Remarks
Dmitry Samarsky, Ph.D., Executive Vice President, Technology Development, RiboBio
Dmitry Samarsky, Ph.D., Executive Vice President, Technology Development, RiboBio
Oligonucleotide Delivery: Mechanisms, Cellular Barriers and Cell/Tissue Targeting
8:30
Mechanism of Cellular Uptake of Single Stranded Oligonucleotides in Mammalian Tissues
There continues to be good progress advancing single stranded, phosphorothioate modified antisense oligonucleotides into the clinic with one approved antisense drug, a second drug submitted for approval and over 25 antisense drugs being evaluated in various clinical trials for a wide spectrum of diseases. The mechanisms through which these antisense drugs accumulate in tissues and gain access to their target RNAs is not well understood. Results will be presented, providing unique insights into how they distribute from the plasma compartment to various intracellular compartments including compartments containing the targeted RNA.
C. Frank Bennett, Ph.D., Senior Vice President, Research, Isis Pharmaceuticals
There continues to be good progress advancing single stranded, phosphorothioate modified antisense oligonucleotides into the clinic with one approved antisense drug, a second drug submitted for approval and over 25 antisense drugs being evaluated in various clinical trials for a wide spectrum of diseases. The mechanisms through which these antisense drugs accumulate in tissues and gain access to their target RNAs is not well understood. Results will be presented, providing unique insights into how they distribute from the plasma compartment to various intracellular compartments including compartments containing the targeted RNA.
C. Frank Bennett, Ph.D., Senior Vice President, Research, Isis Pharmaceuticals
9:00
Cellular Delivery and Activity of LNA Oligonucleotides
LNA oligonucleotides are taken up by cells in vitro and in vivo in an active state without added delivery vehicles. The activity is governed by many factors including oligonucleotide design and cell type. Examples will be given on how biophysical and structural properties drive uptake and potency at the cellular and systemic level.
Bo Rode Hansen, Ph.D., Senior Director, Technology and Partnered Discovery, Santaris Pharma A/S, Denmark
LNA oligonucleotides are taken up by cells in vitro and in vivo in an active state without added delivery vehicles. The activity is governed by many factors including oligonucleotide design and cell type. Examples will be given on how biophysical and structural properties drive uptake and potency at the cellular and systemic level.
Bo Rode Hansen, Ph.D., Senior Director, Technology and Partnered Discovery, Santaris Pharma A/S, Denmark
9:30
Combinatorial Development of siRNA Therapeutics
High-throughput, combinatorial approaches have revolutionized small molecule drug discovery. Here we describe our work on high throughput methods for developing and characterizing biomaterials, and in particular siRNA delivery systems. Libraries of nanoparticles, degradable polymers and lipid-like materials have been synthesized, formulated and screened for their ability to deliver siRNA, both in vitro and in vivo. A number of siRNA delivery formulations have been developed with in vivo efficacy, and show potential therapeutic application for the treatment of genetic disease, viral infection, and cancer.
Daniel G. Anderson, Ph.D., Associate Professor Chemical Engineering, Koch Institute, Massachusetts Institute of Technology
High-throughput, combinatorial approaches have revolutionized small molecule drug discovery. Here we describe our work on high throughput methods for developing and characterizing biomaterials, and in particular siRNA delivery systems. Libraries of nanoparticles, degradable polymers and lipid-like materials have been synthesized, formulated and screened for their ability to deliver siRNA, both in vitro and in vivo. A number of siRNA delivery formulations have been developed with in vivo efficacy, and show potential therapeutic application for the treatment of genetic disease, viral infection, and cancer.
Daniel G. Anderson, Ph.D., Associate Professor Chemical Engineering, Koch Institute, Massachusetts Institute of Technology
10:00
Design and Manufacture of Lipid Nanoparticle Systems for the Systemic Delivery of siRNA
An effective lipid nanoparticle (LNP) siRNA delivery system must exhibit efficient oligonucleotide encapsulation, long circulation lifetimes, preferential accumulation in target tissue, facilitated uptake into target cells and delivery of encapsulated siRNA into the target cell cytoplasm following endocytosis. All this must be accomplished with minimal toxic or immunostimulatory side-effects. In this talk I will summarize the state-of-the-art for engineering LNP systems to achieve these objectives.
Pieter R. Cullis, Ph.D., Director Nanomedicines Research Group and Professor, Department of Biochemistry and Molecular Biology, University of British Columbia, Canada
An effective lipid nanoparticle (LNP) siRNA delivery system must exhibit efficient oligonucleotide encapsulation, long circulation lifetimes, preferential accumulation in target tissue, facilitated uptake into target cells and delivery of encapsulated siRNA into the target cell cytoplasm following endocytosis. All this must be accomplished with minimal toxic or immunostimulatory side-effects. In this talk I will summarize the state-of-the-art for engineering LNP systems to achieve these objectives.
Pieter R. Cullis, Ph.D., Director Nanomedicines Research Group and Professor, Department of Biochemistry and Molecular Biology, University of British Columbia, Canada
10:30
Networking Refreshment Break in Poster and Exhibit Hall
11:15
Role of Chemical Modifications, Conjugation Chemistry and Lipid Nanoparticles in Improving Therapeutic Utility of RNAi
At Alnylam Pharmaceuticals, we have developed and applied multiple chemistry strategies to address the challenge of cellular delivery of drugs that function through RNAi pathways. These include chemical modifications of oligonucleotides, targeted molecular conjugates with appropriate ligands and delivery systems based on liposomal nanoparticles (LNPs). Our progress in these areas will be summarized.
Muthiah Manoharan, Ph.D., Senior Vice President, Drug Discovery, Alnylam Pharmaceuticals, Inc.
At Alnylam Pharmaceuticals, we have developed and applied multiple chemistry strategies to address the challenge of cellular delivery of drugs that function through RNAi pathways. These include chemical modifications of oligonucleotides, targeted molecular conjugates with appropriate ligands and delivery systems based on liposomal nanoparticles (LNPs). Our progress in these areas will be summarized.
Muthiah Manoharan, Ph.D., Senior Vice President, Drug Discovery, Alnylam Pharmaceuticals, Inc.
11:45
Antitumor Efficacy using DsiRNA/LNPs in HCC and Non-HCC Tumor Models
We have developed novel LNP-based formulations, including targeted and non-targeted, with the ability to deliver DsiRNA to xenograft tumors, including both liver and non-liver tumor models. Antitumor efficacy from orthotopic and subcutaneous models will be shown, along with effective strategies to reduce or eliminate immunostimulatory activities of both the RNA payloads and the lipid particles.
Bob D. Brown, Ph.D., CSO and SVP of Research, Dicerna Pharmaceuticals
We have developed novel LNP-based formulations, including targeted and non-targeted, with the ability to deliver DsiRNA to xenograft tumors, including both liver and non-liver tumor models. Antitumor efficacy from orthotopic and subcutaneous models will be shown, along with effective strategies to reduce or eliminate immunostimulatory activities of both the RNA payloads and the lipid particles.
Bob D. Brown, Ph.D., CSO and SVP of Research, Dicerna Pharmaceuticals
12:15
Panel Discussion with Morning Speakers
12:45
Networking Luncheon in Poster and Exhibit Hall
Sponsored by
1:55
Chairperson's Remarks
Troels Koch, Ph.D., Vice President, Research and CTO, Santaris Pharma A/S, Denmark
Troels Koch, Ph.D., Vice President, Research and CTO, Santaris Pharma A/S, Denmark
New Data from Oligonucleotides in Development
2:00
Discovery and Development of Cardiovascular Drug Candidates Based on microRNA Targeting
microRNA's have emerged as an attractive new class of drug targets for a variety of cardiovascular disorders. Genetic deletion studies that have been recapitulated in normal animals by systemically dosing short, high affinity antimiRs provide compelling target validation. A fine tuned analysis of the pharmacological properties of closely related antimiR sequences has provided unique insights on the properties of specific molecules and points to unique drug like characteristics of specific structures.
William S. Marshall, Ph.D., President and Chief Executive Officer, miRagen Therapeutics
microRNA's have emerged as an attractive new class of drug targets for a variety of cardiovascular disorders. Genetic deletion studies that have been recapitulated in normal animals by systemically dosing short, high affinity antimiRs provide compelling target validation. A fine tuned analysis of the pharmacological properties of closely related antimiR sequences has provided unique insights on the properties of specific molecules and points to unique drug like characteristics of specific structures.
William S. Marshall, Ph.D., President and Chief Executive Officer, miRagen Therapeutics
2:30
Progress in Developing microRNA Therapeutics
The ability of microRNAs (miRs) to modulate disease pathways makes targeting them a promising new therapeutic approach. Regulus Therapeutics is taking a systematic approach to create "best in class" anti-miRs by utilizing a combination of novel chemical modifications, bioinformatics and the understanding of tissue and cellular uptake. We will present data highlighting our progress.
Balkrishen Bhat, Ph.D., Senior Director, Chemistry, Regulus Therapeutics
The ability of microRNAs (miRs) to modulate disease pathways makes targeting them a promising new therapeutic approach. Regulus Therapeutics is taking a systematic approach to create "best in class" anti-miRs by utilizing a combination of novel chemical modifications, bioinformatics and the understanding of tissue and cellular uptake. We will present data highlighting our progress.
Balkrishen Bhat, Ph.D., Senior Director, Chemistry, Regulus Therapeutics
3:00
Potent Antisense Pharmacology of Highly Optimized Antisense Oligonucleotides in Multiple Transgenic, Spontaneous and Patient Derived Xenograft Models of Cancer
Despite recent clinical progress, challenges in demonstrating robust antisense pharmacology in preclinical cancer models has slowed the progress of this technology as cancer therapeutics. Here we have employed a high resolution in-situ hybridization-based methodology (Quantigene™) among other detection methods, to demonstrate visually and quantitatively the activity of systemically administered, high potency next generation antisense oligonucleotides, in multiple preclinical cancer models. Cancer models evaluated include, transgenic models, chemically induced tumor, genetically predisposed mouse strains, cell line derived xenograft and patient derived xenograft models.
A. Robert MacLeod, Ph.D., Executive Director, Discovery Biology, Isis Pharmaceuticals, Inc.
Despite recent clinical progress, challenges in demonstrating robust antisense pharmacology in preclinical cancer models has slowed the progress of this technology as cancer therapeutics. Here we have employed a high resolution in-situ hybridization-based methodology (Quantigene™) among other detection methods, to demonstrate visually and quantitatively the activity of systemically administered, high potency next generation antisense oligonucleotides, in multiple preclinical cancer models. Cancer models evaluated include, transgenic models, chemically induced tumor, genetically predisposed mouse strains, cell line derived xenograft and patient derived xenograft models.
A. Robert MacLeod, Ph.D., Executive Director, Discovery Biology, Isis Pharmaceuticals, Inc.
3:30
Networking Refreshment Break in Poster and Exhibit Hall
4:00
Oligonucleotide Conjugates for the Treatment of Neuromuscular Disorders
Prosensa is developing antisense oligonucleotides (AONs) to correct mutated mRNA causing neuromuscular disorders. Their therapeutic use depends on adequate delivery to relevant tissues. Conjugation of AONs to targeting ligands is a potential strategy to enhance AON uptake. In vivo PoC has been recently obtained with a peptide-AON conjugate in a Myotonic Dystrophy mouse model. Further details about efficacy and safety of AON conjugates will be presented.
Begoña Aguilera, Ph.D., Scientific Study Manager, Prosensa Therapeutics BV, The Netherlands
Prosensa is developing antisense oligonucleotides (AONs) to correct mutated mRNA causing neuromuscular disorders. Their therapeutic use depends on adequate delivery to relevant tissues. Conjugation of AONs to targeting ligands is a potential strategy to enhance AON uptake. In vivo PoC has been recently obtained with a peptide-AON conjugate in a Myotonic Dystrophy mouse model. Further details about efficacy and safety of AON conjugates will be presented.
Begoña Aguilera, Ph.D., Scientific Study Manager, Prosensa Therapeutics BV, The Netherlands
4:30
Targeting RTP801: From Discovery to Clinic and Back to Discovery
Intravitreal administration of siRNA targeting RTP801 (a proprietary gene involved in stress regulation of the mTOR pathway) demonstrated local RNAi, lack of inflammatory effects and excellent preclinical and clinical safety profiles. In human Phase IIa DME trial, significant dose-dependent and continuous improvement of visual acuity was observed. Based on these results and the anticipated biological activity, siRTP801 was tested for its ability to induce neuroprotection and/or neuroregeneration in animal models. The results will be discussed.
Elena Feinstein, M.D., Ph.D., Chief Scientific Officer, Quark Pharmaceuticals
Intravitreal administration of siRNA targeting RTP801 (a proprietary gene involved in stress regulation of the mTOR pathway) demonstrated local RNAi, lack of inflammatory effects and excellent preclinical and clinical safety profiles. In human Phase IIa DME trial, significant dose-dependent and continuous improvement of visual acuity was observed. Based on these results and the anticipated biological activity, siRTP801 was tested for its ability to induce neuroprotection and/or neuroregeneration in animal models. The results will be discussed.
Elena Feinstein, M.D., Ph.D., Chief Scientific Officer, Quark Pharmaceuticals
5:00
RNA Targeting by Novel Gene-Silencing Oligonucleotides (GSOs)
GSOs consist of two identical segments complementary to the targeted mRNA attached through their 5'-ends. GSOs of 19- to 21-mer length show optimal gene silencing activity in cell-based assays and following systemic administration, targeted to mRNA or microRNA. In addition, GSOs minimize immune stimulation due to its novel structure, thereby preventing off-target effects. GSOs hold promise as novel gene-silencing agents for systemic applications, without requiring use of carriers.
Nicola La Monica, Ph.D., Vice President of Biology, Idera Pharmaceuticals
GSOs consist of two identical segments complementary to the targeted mRNA attached through their 5'-ends. GSOs of 19- to 21-mer length show optimal gene silencing activity in cell-based assays and following systemic administration, targeted to mRNA or microRNA. In addition, GSOs minimize immune stimulation due to its novel structure, thereby preventing off-target effects. GSOs hold promise as novel gene-silencing agents for systemic applications, without requiring use of carriers.
Nicola La Monica, Ph.D., Vice President of Biology, Idera Pharmaceuticals
5:30
Networking Reception and Booth Crawl in Poster and Exhibit Hall with Dedicated Poster Viewing
Poster presenters are requested to be available at their posters
Poster presenters are requested to be available at their posters
Courses: Sunday | Plenary Sessions: Monday | Main Conference: Tuesday | Wednesday
8:25
Chairperson's Remarks
Michael V. Templin, Ph.D., Senior Vice President, Chief Technology Officer, Marina Biotech
Michael V. Templin, Ph.D., Senior Vice President, Chief Technology Officer, Marina Biotech
Preclinical Chemical Modifications to Improve Drug-Like Properties
8:30
A Target-Focused Approach for Development of Nucleic Acid-Based Therapeutics
Our target-focused approach utilizes unique chemistry (UNA and CRN) and delivery (DiLA2, SMARTICLES, tkRNAi) technologies in the discovery of nucleic acid-based therapeutics to a specific mRNA or a microRNA network. This approach engages RNAi, mRNA translational blocking, and microRNA mechanisms of action; thereby creating a powerful and integrated drug discovery platform to capitalize on the advantages of targeting single or multiple biological pathways.
Michael V. Templin, Ph.D., Senior Vice President, Chief Technology Officer, Marina Biotech
Our target-focused approach utilizes unique chemistry (UNA and CRN) and delivery (DiLA2, SMARTICLES, tkRNAi) technologies in the discovery of nucleic acid-based therapeutics to a specific mRNA or a microRNA network. This approach engages RNAi, mRNA translational blocking, and microRNA mechanisms of action; thereby creating a powerful and integrated drug discovery platform to capitalize on the advantages of targeting single or multiple biological pathways.
Michael V. Templin, Ph.D., Senior Vice President, Chief Technology Officer, Marina Biotech
9:00
High Throughput Synthesis of Multi variant siRNAs for Chemistry Selection and Lead Optimization
Satya Kuchimanchi, Ph.D., Associate Director, RNAi Lead Development, Alnylam Pharmaceuticals, Inc.
Satya Kuchimanchi, Ph.D., Associate Director, RNAi Lead Development, Alnylam Pharmaceuticals, Inc.
9:30
Preclinical Development of ATP0001, a TLR9 Agonist with a Novel Chemical Modification at the CpG Motif and Improved Immune Stimulatory Properties
Synthetic oligonucleotides containing unmethylated CpG motifs are able to stimulate potent immune responses through a signaling pathway involving Toll-like receptor 9 (TLR9). ATP0001 is a preclinical development candidate for use in cancer. It contains a novel chemical modification at the CpG motif resulting in more potent immune stimulatory effects in vitro and in vivo as compared to known TLR9 agonists. We will present efficacy and safety data as well as our plans for a Phase I study to be initiated in 2012.
Eugen Uhlmann, Ph.D., CSO and Co-Founder, AdiuTide Pharmaceuticals GmbH, Germany
Synthetic oligonucleotides containing unmethylated CpG motifs are able to stimulate potent immune responses through a signaling pathway involving Toll-like receptor 9 (TLR9). ATP0001 is a preclinical development candidate for use in cancer. It contains a novel chemical modification at the CpG motif resulting in more potent immune stimulatory effects in vitro and in vivo as compared to known TLR9 agonists. We will present efficacy and safety data as well as our plans for a Phase I study to be initiated in 2012.
Eugen Uhlmann, Ph.D., CSO and Co-Founder, AdiuTide Pharmaceuticals GmbH, Germany
10:00
Opportunities and Challenges in the Development of RNA Therapeutics
The field is making steady advances in discovering and developing novel therapeutics based on RNA interference. This powerful gene-targeting technology has the potential for becoming an important new therapeutic modality, offering a strategy for accessing disease targets previously considered un-druggable with traditional small molecules and biologics. The presentation will showcase case-studies from our lead identification and optimization of siRNAs and delivery vehicles.
Walter Strapps, Ph.D., Senior Research Fellow, Merck & Co, Inc.
The field is making steady advances in discovering and developing novel therapeutics based on RNA interference. This powerful gene-targeting technology has the potential for becoming an important new therapeutic modality, offering a strategy for accessing disease targets previously considered un-druggable with traditional small molecules and biologics. The presentation will showcase case-studies from our lead identification and optimization of siRNAs and delivery vehicles.
Walter Strapps, Ph.D., Senior Research Fellow, Merck & Co, Inc.
10:30
Networking Refreshment Break in Poster and Exhibit Hall
11:15
Lipophilic Phosphate Linkages: An Untapped Approach to Overcoming the Challenges of Delivering Nucleotide Based Therapeutics
LipoSciences has developed a novel suite of RNA and DNA based nucleotide amidites that provide access to charge attenuated synthetic nucleotide therapeutics through a masked phosphate approach. This reversible covalent Triester based technology is sequence and platform independent, capable of integrating well into RNAi, miRNA, LNA and antisense pro-oligo designs. The resulting lipophilic nucleotide mimetic constructs deliver fully functional 2ʹ modified phosphodiester based therapeutic payloads. We will introduce this innovative achievement and discuss our progress towards clinical applications.
Scott Petersen, Ph.D., Chief Scientific Officer, LipoSciences
LipoSciences has developed a novel suite of RNA and DNA based nucleotide amidites that provide access to charge attenuated synthetic nucleotide therapeutics through a masked phosphate approach. This reversible covalent Triester based technology is sequence and platform independent, capable of integrating well into RNAi, miRNA, LNA and antisense pro-oligo designs. The resulting lipophilic nucleotide mimetic constructs deliver fully functional 2ʹ modified phosphodiester based therapeutic payloads. We will introduce this innovative achievement and discuss our progress towards clinical applications.
Scott Petersen, Ph.D., Chief Scientific Officer, LipoSciences
Emerging Preclinical and Clinical Results
11:45
The Development of a miRNA-based Therapeutic Candidate for Hepatocellular Carcinoma
Mimics of five tumor suppressor miRNAs that significantly inhibit the proliferation of multiple hepatocellular carcinoma cell lines were complexed with several lipid formulations and injected into the tail veins of NOD/SCID mice with orthotopically grown Hep3B liver cancer xenografts. Three of the miRNA mimics caused tumor regression when complexed with several different delivery formulations. A development program has been initiated for one of the formulated miRNAs and preliminary toxicology results suggest that the formulated miRNA is non-toxic and non-immunostimulatory.
David Brown, Ph.D., Director of Research, Mirna Therapeutics, Inc.
Mimics of five tumor suppressor miRNAs that significantly inhibit the proliferation of multiple hepatocellular carcinoma cell lines were complexed with several lipid formulations and injected into the tail veins of NOD/SCID mice with orthotopically grown Hep3B liver cancer xenografts. Three of the miRNA mimics caused tumor regression when complexed with several different delivery formulations. A development program has been initiated for one of the formulated miRNAs and preliminary toxicology results suggest that the formulated miRNA is non-toxic and non-immunostimulatory.
David Brown, Ph.D., Director of Research, Mirna Therapeutics, Inc.
12:15
LNA Oligonucleotides as Drugs against Non-Coding RNA's
LNA oligonucleotides can be used to efficiently inhibit single and entire microRNA families in cell cultures and in experimental animals. Miravirsen - the first microRNA targeting drug in man - has recently been shown to significantly and safely to decrease HCV viral load in treatment naïve patients with just 4 weeks of monotherapy.
Henrik Ørum, M.D., Vice President and Chief Scientific Officer, Santaris Pharma A/S, Denmark
LNA oligonucleotides can be used to efficiently inhibit single and entire microRNA families in cell cultures and in experimental animals. Miravirsen - the first microRNA targeting drug in man - has recently been shown to significantly and safely to decrease HCV viral load in treatment naïve patients with just 4 weeks of monotherapy.
Henrik Ørum, M.D., Vice President and Chief Scientific Officer, Santaris Pharma A/S, Denmark
12:45
Networking Luncheon in Poster and Exhibit Hall
Last Chance for Poster and Exhibit Viewing
Last Chance for Poster and Exhibit Viewing
1:55
Chairperson's Remarks
Satya Kuchimanchi, Ph.D., Associate Director, RNAi Lead Development, Alnylam Pharmaceuticals, Inc.
Satya Kuchimanchi, Ph.D., Associate Director, RNAi Lead Development, Alnylam Pharmaceuticals, Inc.
2:00
Considerations in the Development of siRNA Therapeutics
Charles Thompson, Ph.D., Director, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories
Charles Thompson, Ph.D., Director, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories
2:30
Applying Second-Generation Antisense Technology for the Treatment of Cardiovascular Disorders
Second-generation ASOs have been most extensively evaluated in cardiovascular diseases and our most advanced program, Mipomersen, has completed four positive Phase 3 studies, and regulatory submission for drug approval has been completed. In addition, new programs for the treatment of dyslipidemia, thrombosis and cardiomyopathy have entered clinical trials, and proof-of-concept has been achieved in early development. ISIS-APOCIIIrx, a second generation ASO targeting APOCIII in the liver, has now completed Phase I development and has demonstrated strong, dose-dependent efficacy for reducing both APOCIII and triglyceride levels in normal volunteers, with good tolerability. Experience in applying second generation ASOs for cardiovascular diseases will be presented.
Richard Lee, Ph.D., Assistant Director, Antisense Drug Discovery, Isis Pharmaceuticals, Inc.
Second-generation ASOs have been most extensively evaluated in cardiovascular diseases and our most advanced program, Mipomersen, has completed four positive Phase 3 studies, and regulatory submission for drug approval has been completed. In addition, new programs for the treatment of dyslipidemia, thrombosis and cardiomyopathy have entered clinical trials, and proof-of-concept has been achieved in early development. ISIS-APOCIIIrx, a second generation ASO targeting APOCIII in the liver, has now completed Phase I development and has demonstrated strong, dose-dependent efficacy for reducing both APOCIII and triglyceride levels in normal volunteers, with good tolerability. Experience in applying second generation ASOs for cardiovascular diseases will be presented.
Richard Lee, Ph.D., Assistant Director, Antisense Drug Discovery, Isis Pharmaceuticals, Inc.
3:00
A Single PMOplus oligomer is Effective in a Rhesus Macaque Ebola Zaire Virus Lethal Challenge Model
INTRODUCTION. Ebolavirus (EBOV) is a highly virulent RNA virus of the family Filoviridae and a causative agent of viral hemorrhagic fever (VHF). PMOplus oligomers targeting VP35 and VP24 in the Ebola Zaire (ZEBOV) virus were effective in mouse and guinea pig lethal challenge models. OBJECTIVE. The current study was to determine the contributions of oligomers targeting VP35 and VP24 individually versus the combination of the two in a rhesus macaque(NHP) ZEBOV lethal challenge model. METHODS. A blinded study was conducted in which NHP were infected with a target dose of 1000 pfu of ZEBOV administered intramuscularly. Viral genomic RNA was obtained from infected animals immediately upon sample collection by mixing one volume of serum with three volumes of Triazol LS. Samples with > 300 pfu/mL were amplified using random hexamer DNA primers and reverse transcriptase PCR amplification. Viral genome sequence was determined using pyrosequencing methods for deep sequence analysis. RESULTS. The study involved 4 groups; group 1 = 8 NHP with VP35 and VP24, group 2 = 8 NHP with VP24 only, group 3 = 8 NHP with VP35 only with all oligomers dosed at 40 mg/kg administered daily by the iv route, and group 4 = 6 NHP administered saline. Survival was determined at 40 to 43 days post infection. Survival observations included 5/8 (63%) in group 1 targeting VP35 and VP24, 6/8 (75%) in group 2 targeting VP24, 0/8 (0%) in group 3 targeting VP35, and 0/6 (0%) in the saline control group. CONCLUSIONS. We conclude the single PMOplus oligomer (AVI-7537) targeting VP24 is the optimal single agent for protection against a ZEBOV lethal challenge in NHP.
Patrick Iversen, Ph.D., Senior Vice President, Research and Innovation, AVI BioPharma
INTRODUCTION. Ebolavirus (EBOV) is a highly virulent RNA virus of the family Filoviridae and a causative agent of viral hemorrhagic fever (VHF). PMOplus oligomers targeting VP35 and VP24 in the Ebola Zaire (ZEBOV) virus were effective in mouse and guinea pig lethal challenge models. OBJECTIVE. The current study was to determine the contributions of oligomers targeting VP35 and VP24 individually versus the combination of the two in a rhesus macaque(NHP) ZEBOV lethal challenge model. METHODS. A blinded study was conducted in which NHP were infected with a target dose of 1000 pfu of ZEBOV administered intramuscularly. Viral genomic RNA was obtained from infected animals immediately upon sample collection by mixing one volume of serum with three volumes of Triazol LS. Samples with > 300 pfu/mL were amplified using random hexamer DNA primers and reverse transcriptase PCR amplification. Viral genome sequence was determined using pyrosequencing methods for deep sequence analysis. RESULTS. The study involved 4 groups; group 1 = 8 NHP with VP35 and VP24, group 2 = 8 NHP with VP24 only, group 3 = 8 NHP with VP35 only with all oligomers dosed at 40 mg/kg administered daily by the iv route, and group 4 = 6 NHP administered saline. Survival was determined at 40 to 43 days post infection. Survival observations included 5/8 (63%) in group 1 targeting VP35 and VP24, 6/8 (75%) in group 2 targeting VP24, 0/8 (0%) in group 3 targeting VP35, and 0/6 (0%) in the saline control group. CONCLUSIONS. We conclude the single PMOplus oligomer (AVI-7537) targeting VP24 is the optimal single agent for protection against a ZEBOV lethal challenge in NHP.
Patrick Iversen, Ph.D., Senior Vice President, Research and Innovation, AVI BioPharma
3:30
Networking Refreshment Break
4:00
Pre-Clinical and Early Clinical Characterization of the SDF-1 Inhibitor NOX-A12 for its Applications in Certain Types of Leukemia
NOX-A12 is a high affinity Spiegelmer directed to bind and inhibit stromal-cell derived factor-1 (SDF-1). SDF-1 plays an important role in the homing and recruitment of stem cells as well as malignant stem cells. NOX-A12 has been preclinically active in vitro and in vivo models for certain types of leukemia. Clinical data suggest an efficient interference with the homing process of stem cells. Thus, NOX-A12 will now be characterized in patients suffering from leukemia.
Axel Vater, Ph.D., Vice President Drug Discovery, NOXXON Pharma AG, Germany
NOX-A12 is a high affinity Spiegelmer directed to bind and inhibit stromal-cell derived factor-1 (SDF-1). SDF-1 plays an important role in the homing and recruitment of stem cells as well as malignant stem cells. NOX-A12 has been preclinically active in vitro and in vivo models for certain types of leukemia. Clinical data suggest an efficient interference with the homing process of stem cells. Thus, NOX-A12 will now be characterized in patients suffering from leukemia.
Axel Vater, Ph.D., Vice President Drug Discovery, NOXXON Pharma AG, Germany
4:30
REP 9AC Induces a Sustained Virologic Response in Human Patients with Chronic Hepatitis B Infection
REP 9AC is a 40mer PS-ON [(AC)20] which blocks HBV subviral particle release from infected hepatocytes. Subviral particles deliver surface antigen protein (HBsAg) to the blood which inhibits the antiviral immune response, allowing HBV infection to persist. Preclinical and early clinical studies show that REP 9AC is generally well tolerated, clears HBsAg from the blood and allows patients with HBV infection to achieve SVRs with relatively short term treatment paradigms. These interim clinical results suggest that REP 9AC may be an important new tool in the treatment of HBV infection.
Andrew Vaillant, Ph.D., Chief Scientific Officer, REPLICor, Inc., Canada
REP 9AC is a 40mer PS-ON [(AC)20] which blocks HBV subviral particle release from infected hepatocytes. Subviral particles deliver surface antigen protein (HBsAg) to the blood which inhibits the antiviral immune response, allowing HBV infection to persist. Preclinical and early clinical studies show that REP 9AC is generally well tolerated, clears HBsAg from the blood and allows patients with HBV infection to achieve SVRs with relatively short term treatment paradigms. These interim clinical results suggest that REP 9AC may be an important new tool in the treatment of HBV infection.
Andrew Vaillant, Ph.D., Chief Scientific Officer, REPLICor, Inc., Canada
5:00
Close of Conference
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