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Oligonucleotide Therapeutics and Delivery 2016
- 寡核酸之治疗与传导学会 2016年 -
2016年4月4日 - 2016年4月5日
美国,马萨诸塞州,剑桥,Hyatt Regency

Oligonucleotide Therapeutics and Delivery


寡核酸药物长期以来就被列为医药品开发之第三个重要平台,并且特别聚焦在透过RNA与基因组自身标的化之基因表现调节技术。核酸作为药物的主要特徵在于其能够到达小分子药物及生物制剂所不可及的undruggable领域,因而能够透过药物开发来对抗诸如疗法受限或无特定疗法之各种疾病。对核酸药物领域之关注虽大幅提升,但因第一世代分子在效能与安全层面上仍存在些许课题,因此对医药品开发仍未造成戏剧性的广泛影响。在近年核酸化学与传导技术之进步下,稳定性、生体可用率(Bioavailability)、特异性、效能已渐获改善,普遍认为在短期内可成功开发新一代药物,并在临床阶段获得正面评价。

Oligonucleotide Therapeutics and Delivery将在2016年4月4日至5日于美国麻萨诸塞州剑桥举办,医药品开发及创药之主要研究人员均将莅临,针对寡核酸药物所衍生之技术面与科学面发展进行讨论。

  

4月4日 (一)

 

7:00 报名手续、咖啡

 


治疗用寡核酸之进展

8:10 主席开幕致词

Dmitry Samarsky, Ph.D., Senior Vice President, Technology Development, RiboBio Co, China

8:15 主题演讲:作为寡核酸治疗新典范之N-乙醯半乳醣胺N-acetylgalactosamine (GalNAc) 共轭的siRNA

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 核酸治疗之发展

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 治疗遗传性疾病与传染病之Phosphorodiamidate Oligomers (PMOs)

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 赞助商简报 (徵求演讲者)

10:15 展场大厅休息、参观海报发表

 

合成与医化学

10:45 特别演讲:有关与三价体GalNAc共轭之反义寡核酸的构造活性

Punit Seth, Ph.D., Executive Director, Medicinal Chemistry, 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 因应RNA药物之phosphorodithioate RNA

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 能够稳定Guanine鸟嘌呤的四重锁构造、并强化白血病细胞内成长阻碍活性之c-Myc Promoter标的化寡核酸脂质修饰

Gilles Tapolsky, Ph.D., CSO, Advanced Cancer Therapeutics

We have shown that Pu27 reduces c-MYC transcription in leukemia cell lines and consequently inhibits cell growth and promotes apoptosis. In this study, we evaluated the effect of Pu27 modification using polyethylene glycol (PEG), tocopherol (Toco) and the lipid palmitate in order to increase G-quadruplex stability and lessen blood clearance. Our finding suggests that modification of the c-MYC targeted oligonucleotide by addition of lipids stabilizes the 3D structure (G-quadruplex) and improve its function at inhibiting cell growth most likely by down-regulating c-MYC.

12:15 简报午餐会或各自用膳

 

癌症免疫疗法与合并疗法

1:25 主席发言

Art Krieg, M.D., Founder and CEO, Checkmate Pharma

1:30 特别演讲:Check Point抑制疗法之有效率提升可能性:TLR9扮演之角色

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 利用肿瘤内imo-2125 (TLR9致效剂)进行肿瘤微环境之调节,可透过与Check Point抑制剂之合并使用达到有效治疗

Sudhir Agrawal, D.Phil., President, Research, Idera Pharmaceuticals

 

2:30 CureVac之序列最佳化mRNA-次世代生物制剂开发方式

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 展场大厅休息、参观海报发表

 

3:30 利用RNAi之免疫Check Point之Silencing

Alexey Wolfson, Ph.D., Founder and CSO, MirImmune

 

4:00 具备免疫调节功能之球形核酸

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 赞助商简报(徵求演讲者)

5:00 展场大厅迎宾接待、参观海报发表

6:00 第一天结束


4月5日 (二)

7:30 分组讨论早餐会

 

抗病毒剂之开发

8:25 主席发言

Andrew Vaillant, Ph.D., CSO, Replicor Inc.

8:30 核酸聚合物:在慢性B型肝炎、B型肝炎/D型肝炎传染病治疗上的抗病毒作用机转与应用

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 慢性B型肝炎传染病与因子12因应媒介疾病之RNAi药物中有关DPC技术的应用

David Lewis, Ph.D., CSO, Arrowhead Research Corporation

9:30 赞助商演讲(徵求演讲者)

9:45 展场大厅休息、参观海报发表

 

RNA药物与传导技术之进展

10:25 主席发言

Balkrishen (Bal) Bhat, Ph.D., Vice President, Chemistry, RaNA Therapeutics

10:30 长Non-Coding RNA (lncRNA) :医药品开发之新领域

Balkrishen (Bal) Bhat, Ph.D., Vice President, Chemistry, RaNA Therapeutics

The ss-siRNA activity in vivo requires a metabolically stable 5'-phosphate analog. Here, we used crystal structure of the 5'-phosphate binding pocket of Ago-2 bound with guide strand to design and synthesize ss-siRNAs containing various 5'-phosphate analogs. Chemically modified ss-siRNA targeting human apoC III mRNA demonstrated good potency for inhibiting ApoC III mRNA and protein in transgenic mice. Moreover, ApoC III ss-siRNAs were able to reduce the triglyceride and LDL cholesterol in transgenic mice demonstrating pharmacological effect of ss-siRNA.

11:00 基于专有的miRNA独特作用之新突破性癌症疗法开发

Roel Q.J. Schaapveld, Ph.D., MBA, CEO, InteRNA Technologies BV

To explore miRNAs as therapeutic angiogenesis-inhibitors, we performed a functional screen to identify miRNAs that are able to decrease EC viability. We identified miRNA-7 (miR-7) as a potent negative regulator of angiogenesis. This study provides a comprehensive validation of miR-7 as novel anti-angiogenic therapeutic miRNA that can be systemically delivered to both EC and tumor cells and offers promise for miR-7 as novel anti-tumor therapeutic.

11:30 以脂质为基础之寡核酸传导系统开发

Volker Fehring, Ph.D., Director, Formulation Development, Silence Therapeutics GmbH

Posttranscriptional gene silencing by RNA interference can be therapeutically exploited to inhibit pathophysiological gene expression. However, in contrast to the established effectiveness of RNAi in vitro, safe and effective delivery of siRNAs to specific organs and cell types in vivo remains the major hurdle. Here, we report the development and in vivo characterization of a novel siRNA delivery system (DACC lipoplex) suitable for modulating target gene expression.

12:00 简报午餐会或各自用膳

 

对中枢神经之传导

1:00 主席发言

Dong-ki Lee, Ph.D., Professor, Sungkyunkwan University, South Korea; CEO, OliX Pharmaceuticals

1:05 鼻腔投药后与血清素 Serotonin运送体之Silencing共轭之siRNA在抗忧郁剂之可能性

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 以治疗神经退化疾病之寡核酸外泌体为媒介之传导

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.


针对生物体内传导之新手法

2:05 特别讲演:使用第2代RNAi Trigger之药品开发

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 因应寡核酸之创药与传导之展新Nano Medicine平台

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 展场大厅休息、参观海报发表

3:45 因应来自多个病患之异种移植肿瘤的Dicer-Substrate siRNA (DsiRNA) 传导

Bob Brown, Ph.D., CSO, Dicerna Pharmaceuticals

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. However, while LNPs are well characterized for delivery of RNA oligonucleotides to the normal liver, much remains to be explored regarding the mechanisms of LNP-mediated delivery to tumors. In this study, we investigated the ability of Dicerna's unique LNP platform, termed EnCore, to deliver Dicer- substrate siRNAs (DsiRNAs) to xenograft tumors of diverse origin.

4:15 以Messenger RNA为基础之药品从临床前研究迈向临床研究之发展

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 抑制疤痕形成之RXI-109的临床开发

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 强化寡核酸药理作用之小分子

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 学会闭幕

 

* 活动内容有可能不事先告知作更动及调整。



Image Credit: Luminous BioSciences

Luminous BioSciences offers high quality custom DNA oligos that are sunthesized according to your needs. We provide DNA oligo synthesis from 10 base to 200 bases.
www.luminousbio.com


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