Chairs：TakanoriYokota
DepartmentofNeurologyandNeurological Science,TokyoMedicalandDental
University,Japan
YoshitsuguAoki
DepartmentofMolecularTherapy,National InstituteofNeuroscience,NationalCenterof NeurologyandPsychiatry（NCNP）,Japan
≪Objective≫
First antisense oligonucleotide drug, Nesinersen, was approved for spinal muscular atrophy by FDA in December, 2017. Recent progress of basic science and clinical application of oligonucleotide drugs are reviewed and its future development is discussed.
HT-02-1 Engineering selectivity into therapeutic oligonucleotides
through chemical design
○ PunitP.Seth
Ionis Pharmaceuticals, Inc., Canada
【Curriculum Vitae】
Dr.PunitP.SethheadsmedicinalchemistryatIonisPharmaceuticals.
Dr.Sethisco-inventorofIonis'Gen2.5platformwhichemployshigh affinitynucleosidemodificationstoenhancetheaffinity,stability andpotencyofASOsintheliverandinextra-hepatictissues.He isalsotheco-inventorofIonis'LICA（ligandconjugatedantisense oligonucleotides）platformwhichenhancesASOpotencyby targeteddeliverytocellsandtissuesofinterest.Hehasextensive experiencewithusingmedicinalchemistrystrategiestomodulate theactivity,pharmacokineticsandtoxicologicalpropertiesof oligonucleotidedrugs.Dr.Sethislistedasco-author/co-inventoron over170peer-reviewedpublicationsandissuedpatentsandpatent applications.HehasaPh.DinorganicchemistryfromTheOhio StateUniversity.
The fi eld of nucleic acid based therapeutics has seen rapid growth in the last decade. Two Antisense oligonucleotides
（ASOs）, Kynamro and Spinraza, were approved by the FDA recently and two additional ASOs, Inotersen and Volanosersen, completed successful phase 3 trials in 2017. In parallel to these developments, significant progress has been made in understanding the pathways by which ASOs distribute to cells and tissues and on using medicinal chemistry strategies to modulate these processes to further improve ASO potency in the clinic.
Furthermore, medicinal chemistry strategies have also been used to enhance ASO specificity for applications such as allele selective gene silencing for the treatment of autosomal dominant disorders. In this talk, we will discuss recent advances in ASO technology which have enabled the design of more potent and specifi c drugs and for the targeted delivery of ASOs to specifi c cell-types and tissues to further enhance potency and therapeutic index.
Co-hostedby:NucleicAcidsTherapeuticsSociety ofJapan
23 日 シ ン ポ ジ ウ ム
ホットトピックス 02
5月23日（水）13：20 ～ 15：10 第9会場 (ロイトン札幌2F リージェント・ホール)
公募 En
HT-02-2 Antisense therapy for Fukuyama congenital muscular dystrophy
○ TatsushiToda
Department of Neurology, Graduate School of Medicine, The University of Tokyo, Japan
【Curriculum Vitae】
2017- Professor, Department of Neurology, Graduate School of Medicine, University of Tokyo.
2009-2017 Professor, Division of Neurology / Molecular Brain Science, Kobe University Graduate School of Medicine
2000-2009 Professor, Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine
1996-2000 Associate Professor, Human Genome Center, Institute of Medical Science, University of Tokyo
1994-1996 Assistant Professor, Department of Human Genetics, Graduate School of Medicine, University of Tokyo
1985-1994 Medical Doctor, Department of Neurology, University of Tokyo 1985 graduated from University of Tokyo, Faculty of Medicine Member of the Science Council of Japan
[Awards]
1999 Award of Japanese Society of Human Genetics 2001 Award of Japan Foundation for Aging and Health 2002 Award of Societas Neurologica Japonica 2008 Asahi Award
2009 Award from Japanese Minister of Education, Culture, Sports, Science and Technology
2012 Tokizane Memorial Award 2017 Japan Academy Prize
Fukuyama muscular dystrophy （FCMD） and muscle-eye-brain
（MEB） disease are similar disorders characterized by congenital muscular dystrophy, brain and eye anomalies. Hypoglycosylation of a-dystroglycan （a-DG） are common characteristics of these dystroglycanopathies. We identified the genes for FCMD
（fukutin） and MEB （POMGnT1）. FCMD is the first human disease found to result from ancestral insertion of a SVA retrotransposon. We show that aberrant mRNA splicing, induced by SVA exon-trapping, underlies the molecular pathogenesis of FCMD. Introduction of antisense oligonucleotides （AONs）
targeting the splice acceptor, the predicted exonic splicing enhancer and the intronic splicing enhancer prevented pathogenic exon-trapping by SVA in cells of patients with FCMD and model mice, rescuing normal fukutin mRNA expression and protein production. AON treatment also restored fukutin functions, including O-glycosylation of a-DG and laminin binding by a-DG. Thus, we have demonstrated the promise of splicing modulation therapy as the first radical clinical treatment for FCMD.Recently we identified the previously unknown glycan unit ribitol 5-phosphate （Rbo5P）, a phosphoric ester of pentose alcohol, as a tandem repeat that functions as a scaffold for the formation of the ligand-binding moiety of α -DG. We determined the enzyme activities of three major α -DGpathy-causing proteins to be involved in the synthesis of tandem Rbo5P. ISPD is cytidine diphosphate ribitol （CDP-Rbo） synthase. Fukutin and fukutin-related protein are Rbo5P transferases that use CDP-Rbo. Consequently, Rbo5P glycosylation is defective in α-DGpathy models. Supplementation of CDP-Rbo to ISPD-deficient cells restored α-DG glycosylation.
These findings expand our knowledge on post-translational modification, and reveal the pathogenesis and therapeutic strategies of α-DG-associated diseases.
HT-02-3 Recent progress of DNA/RNA heteroduplex oligonucleotide
○ TetsuyaNagata
Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Japan
【Curriculum Vitae】
2018-Current
Research Associate Professor, Department of Neurology,
Department of Neurology and Neurological Science, Tokyo Medical and Dental University
2014-2018
Research Senior Assistant Professor, Department of Neurology, Department of Neurology and Neurological Science, Tokyo Medical and Dental University
2009-2014
Section chief, Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry 2008
Assistant Professor, Department of Neurology, Okayama University School of Medicine
2005-2008
Postdoctoral fellow, Department of Neurology/Center for Motor Neuron Biology and Disease, Columbia University
2003-2005
Assistant Professor, Department of Neurology, Okayama University School of Medicine
1999
Graduated from Tohoku University Graduate School 1994
Graduated from Tohoku University School of Medicine
The rapid expansion of the available genomic data greatly impacts biomedical science and medicine. These genetic discoveries require the development of therapeutics that can regulate the expression of disease-relevant genes. The oligonucleotide therapeutics field has seen remarkable progress over the last few years with the approval of the antisense oligonucleotide （ASO） drugs including splice switching oligonucleotides and with promising developments in late stage clinical trials using siRNA. Despite progress in the oligonucleotide therapeutics, methods which further increase potency of oligonucleotide drugs and improve safety and tolerability are highly desirable. Here we developed a DNA/RNA heteroduplex oligonucleotide （HDO） with a structure different from that of the conventional oligonucleotides for gene silencing, double-stranded RNA of siRNA and single-stranded DNA of ASO. When the DNA strand was used as an ASO and the RNA strand was conjugated with α-tocopherol, it achieved silencing ability about more than 20 times that of ASO alone and can amplify effect of any reported ASOs. The enhanced silencing ability included HDO effects as well as delivery effect of α-tocopherol to the liver. Since the HDO has a specific intracellular processing machinery, we think that HDO is a brand new type oligonucleotide drug. Although delivery organ of HDO was still limited to the liver, we recently developed modified structure of HDO with administration method, which can regulate many extra-hepatic organs, such as heart, kidney, spleen, lung, adrenal gland and subcutaneous adipose tissue and skeletal muscle as a second break of HDO.
23 シ ン ポ ジ ウ ム 日 ホットトピックス 02
5月23日（水）13：20 ～ 15：10 第9会場 (ロイトン札幌2F リージェント・ホール)
公募 En
Chairs：TakanoriYokota
DepartmentofNeurologyandNeurological Science,TokyoMedicalandDental
University,Japan
YoshitsuguAoki
DepartmentofMolecularTherapy,National InstituteofNeuroscience,NationalCenterof NeurologyandPsychiatry（NCNP）,Japan
≪Objective≫
First antisense oligonucleotide drug, Nesinersen, was approved for spinal muscular atrophy by FDA in December, 2017. Recent progress of basic science and clinical application of oligonucleotide drugs are reviewed and its future development is discussed.
HT-02-1 Engineering selectivity into therapeutic oligonucleotides
through chemical design
○ PunitP.Seth
Ionis Pharmaceuticals, Inc., Canada
【Curriculum Vitae】
Dr.PunitP.SethheadsmedicinalchemistryatIonisPharmaceuticals.
Dr.Sethisco-inventorofIonis'Gen2.5platformwhichemployshigh affinitynucleosidemodificationstoenhancetheaffinity,stability andpotencyofASOsintheliverandinextra-hepatictissues.He isalsotheco-inventorofIonis'LICA（ligandconjugatedantisense oligonucleotides）platformwhichenhancesASOpotencyby targeteddeliverytocellsandtissuesofinterest.Hehasextensive experiencewithusingmedicinalchemistrystrategiestomodulate theactivity,pharmacokineticsandtoxicologicalpropertiesof oligonucleotidedrugs.Dr.Sethislistedasco-author/co-inventoron over170peer-reviewedpublicationsandissuedpatentsandpatent applications.HehasaPh.DinorganicchemistryfromTheOhio StateUniversity.
The fi eld of nucleic acid based therapeutics has seen rapid growth in the last decade. Two Antisense oligonucleotides
（ASOs）, Kynamro and Spinraza, were approved by the FDA recently and two additional ASOs, Inotersen and Volanosersen, completed successful phase 3 trials in 2017. In parallel to these developments, significant progress has been made in understanding the pathways by which ASOs distribute to cells and tissues and on using medicinal chemistry strategies to modulate these processes to further improve ASO potency in the clinic.
Furthermore, medicinal chemistry strategies have also been used to enhance ASO specificity for applications such as allele selective gene silencing for the treatment of autosomal dominant disorders. In this talk, we will discuss recent advances in ASO technology which have enabled the design of more potent and specifi c drugs and for the targeted delivery of ASOs to specifi c cell-types and tissues to further enhance potency and therapeutic index.
Co-hostedby:NucleicAcidsTherapeuticsSociety ofJapan
23 日 シ ン ポ ジ ウ ム
ホットトピックス 02
5月23日（水）13：20 ～ 15：10 第9会場 (ロイトン札幌2F リージェント・ホール)
公募 En
HT-02-4 A first Antisense
Oligonucleotide （ASO）
therapy, Nusinersen, for Spinal Muscular Atrophy
○ ShinichiTorii
Biogen Japan Ltd., Japan
【Curriculum Vitae】
March, 1984 Graduated from Gifu College of Pharmacy March, 2002 Ph.D degree from Molecular Biology from Tokyo
University, Graduate School April, 1984 ～ Janssen Pharmaceutical K.K.
April, 2007 ～ Celgene Corporation April, 2010 ～ Olympus Corporation
January, 2011 ～ Chief Scientific Officer (CSO), Olympus Biotech Corporation (Boston, USA)
June, 2014 ～ Head of R&D, Biogen Japan Inc.
April, 2017 ～ President & Representative Director, Biogen Japan Inc.
Spinal Muscular Atrophy （SMA） is severe genetic neuromuscular disease affecting infant and children in the world. SMA is categorized as a genetic rare disease that affects approximately 30-35K children in Japan, United States, and Europe and currently number one genetic cause of death in infants. SMA is also characterized by progressive muscle atrophy and loss of motor function in early days after child-birth. The disease is caused by genetic defects in the SMN1 gene on 5q13 chromosome that result in the lack of functional matured SMN protein and No currently approved therapies is available for SMA.
A related gene, SMN2, normally produces only a small amount of functional SMN protein because of inappropriate RNA processing as biological alternative splicing system.
SMN2 gene cannot produce enough functional SMN protein to compensate for loss of SMN1 gene in patients with SMA because of that Splicing-out mechanism removes exon 7 resulting in a truncated and shortened defective SMN protein.
Antisense oligonucleotides （ASO）, Nusinersen, keeps exon 7 in the RNA and leads to the production of functional SMN protein and increases the production of functional SMN protein by promoting appropriate RNA processing to positively Impact Disease. A number of global clinical study have been performed using IT administration and those results in infant （Type 1） and children （Type 2 and 3） SMA patients are to be presented.
Antisense oligonucleotides -drugs, including Nusinersen, are have broad potential for the treatment of severe neurological diseases. Currently, scientific approaches are being made in antisense technology for Amyotrophic lateral sclerosis （ALS）, Parkinson disease （PD） and Alzheimer's disease （AD）, those are currently under development.
23 日 シ ン ポ ジ ウ ム
ホットトピックス 03
5月24日（木）8：00 ～ 9：30 第2会場 (さっぽろ芸術文化の館3F 瑞雪の間)
Jp
座長：武田 篤
国立病院機構仙台西多賀病院神経 内科森 悦朗
大阪大学大学院連合小児発達学研 究科行動神経学・神経精神医学寄 附講座≪ねらい≫
パーキンソン病運動症状に対する治療の進歩に伴い、パーキ ンソン病患者の生命予後が大きく改善したが、あらたに認知 症が大きな問題となってきている。本シンポジウムでは、パー キンソン病における軽度認知機能障害および認知症の疫学、
レビー小体病における多彩な症状の経時的変化、認知機能低 下に伴う脳機能画像での変化、さらにパーキンソン病認知症 の予防に向けた最近の研究などについての理解を深め、これ からのパーキンソン病治療戦略について活発な議論を期待し ている。