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Oligonucleotide Therapeutics and Delivery 2016
- 治療用オリゴヌクレオチド・デリバリー学会 2016年 -
2016年4月4日 - 2016年4月5日
米国、マサチューセッツ州ケンブリッジ、ハイアット リージェンシー

Oligonucleotide Therapeutics and Delivery


オリゴヌクレオチドベースの治療薬は、以前から医薬品開発における第3の重要なプラットフォームとなっており、とりわけRNAやゲノム自体を標的化することで遺伝子発現を調節する技術は焦点の1つとなっています。治療薬としての核酸の重要な特徴は、小分子薬剤や生物製剤では不可能な領域にも対応できるという点にあり、治療法が限られている、あるいは存在しないような領域を含む多種多様な疾病を治療するための医薬品を開発することが可能です。このため、この分野への関心は大いに高まりましたが、第1世代の分子は、効能と安全性の面で問題を抱えていたため、医薬品開発の世界に劇的な影響を及ぼすには至りませんでした。しかし、近年の核酸化学やデリバリー技術の進歩によって、安定性、バイオアベイラビリティ (生物学的利用能) 、特異性、効能などが改善されたことにより、成功が見込める新世代の治療薬を短期間で開発し、臨床での評価を受けることが可能になっています。

2016年4月4日から5日まで米国マサチューセッツ州ケンブリッジで開催されるOligonucleotide Therapeutics and Deliveryでは、医薬品開発と創薬に携わっている主要な研究者が顔を揃え、オリゴヌクレオチドベースの治療薬に生かされている技術面と科学面の進歩などをめぐって議論を展開します。

  

4月4日 (月)

 

7:00 登録手続き、コーヒー

 


治療用オリゴヌクレオチドの進歩

8:10 議長による開会の挨拶

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

8:15 基調講演:オリゴヌクレオチド治療薬の新たなパラダイムとしてのN-アセチルガラクトサミン (GalNAc) 共役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 立体的に純粋な核酸治療薬の開発

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 遺伝病と感染症の治療に対応する新たなホスホロジアミデートオリゴマー (PMO)

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 スポンサー提供のプレゼンテーション (講演者を募集しています)

10:15 展示会ホールでの休憩、ポスター発表の見学

 

合成と医化学

10:45 特別講演:三価GalNAc共役アンチセンスオリゴヌクレオチドの構造活性相関

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 RNAベースの治療薬に対応するホスホロジチオエート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 グアニン四重鎖構造を安定させ、白血病細胞内での成長阻害活性を強化するc-Mycプロモーター標的化オリゴヌクレオチドの脂質修飾

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 プレゼンテーションを聞きながらの昼食会または各自で昼食

 

がんの免疫療法と併用療法

1:25 議長の発言

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

1:30 特別講演:チェックポイント阻害療法の奏効率向上の可能性:TLR9の役割

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 チェックポイント阻害剤との併用による効果的な治療を可能にする腫瘍内のimo-2125 (TLR9アゴニスト) を利用した腫瘍微小環境の調節

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

 

2:30 CureVacの配列最適化mRNA−次世代生物製剤の開発に向けた取り組み

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 展示会ホールでの休憩、ポスター発表の見学

 

3:30 RNAiを利用した免疫チェックポイントのサイレンシング

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

 

4:00 免疫調節機能を有する球形核酸

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 スポンサー提供のプレゼンテーション (講演者を募集しています)

5:00 展示会ホールでの歓迎レセプション、ポスター発表の見学

6:00 1日目終了


4月5日 (火)

7:30 朝食をとりながらのグループ討論

 

抗ウィルス剤の開発

8:25 議長の発言

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

8:30 核酸ポリマー:慢性B型肝炎、B型肝炎/D型肝炎感染症治療での抗ウィルス機序と応用

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型肝炎感染症と因子12媒介疾患に対応するRNAi治療薬でのDPC技術の利用

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

9:30 スポンサー提供のプレゼンテーション (講演者を募集しています)

9:45 展示会ホールでの休憩、ポスター発表の見学

 

RNAベースの治療薬とデリバリー技術の進歩

10:25 議長の発言

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

10:30 長鎖ノンコーディングRNA (lncRNA) :医薬品開発の新たな領域

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 プロプライエタリマイクロRNAのユニークな機能をベースにした新規の飛躍的ながん治療法の開発

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 脂質ベースのオリゴヌクレオチドデリバリーシステムの開発

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 プレゼンテーションを聞きながらの昼食会または各自で昼食

 

中枢神経系へのデリバリー

1:00 議長の発言

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

1:05 鼻内投与後にセロトニン輸送体のサイレンシングを行う共役siRNAの治療用抗うつ剤としての可能性

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 神経変性疾患の治療に対応する治療用オリゴヌクレオチドのエクソソームを媒介としたデリバリー

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.


生体内でのデリバリーに対する新たなアプローチ

2:05 特別講演:第2世代RNAiトリガーを利用した治療薬の開発

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 オリゴヌクレオチドの創薬とデリバリーに対応する新たなナノメディシンプラットフォーム

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 展示会ホールでの休憩、ポスター発表の見学

3:45 複数の患者に由来する異種移植片腫瘍に対するダイサーサブストレートsiRNA (DsiRNA) のデリバリー

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 メッセンジャーRNAをベースにした治療薬の前臨床研究から臨床研究への展開

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 瘢痕形成を抑えるRXI-109の臨床開発

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 オリゴヌクレオチドの薬理作用を強化する小分子

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 学会閉幕

 

* 不測の事態により、事前の予告なしにプログラムが変更される場合があります。



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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