Chairs：
Satoshi Kuwabara(Department of Neurology, Chiba University)
Haruki Koike(Department of Neurology, Nagoya University Graduate School of Medicine)
≪Objective≫
Our understanding on pathophysiology, genetics, and management of a variety of peripheral neuropathies has been increasing. The simpojium focuses on current status and perspective of pathophysiology and novel treatments of metabolic and hereditary neuropathies, such as amyloid neuropathy, POEMS syndrome, drug-induced neuropathy, and Charcot-Marie-Tooth disease. Paricularly neurologists should be more intensively involved in the diagnosis and management of chemptherapy-induced neuropathy.
HT-03-1
Cutting-edge therapies for amyloid neuropathy
Department of Medicine (Neurology & Rheumatology), Shinshu University School of Medicine
○Yoshiki Sekijima
The amyloidoses are a large group of postsecretory protein misfolding and deposition diseases. The misfolding and misassembly of 31 secreted human proteins are linked to amyloidosis.Transthyretin (TTR), a homotetrameric protein, is a representative amyloidogenic protein in humans. Rate-limiting tetramer dissociation and rapid monomer misfolding and misassembly of variant TTR result in autosomal dominant hereditary ATTR amyloidosis (also called familial amyloid polyneuropathy). The current standard first-line treatment of herediaty ATTR amyloidosis is liver transplantation, which allows suppression of the main source of variant TTR. However, liver transplantation has a number of limitations. Furthermore, large numbers of patients are not good transplant candidates because of their age and/or advanced disease status. Recently, the clinical effects of TTR tetramer stabilizers, tafamidis and diflunisal, were demonstrated in randomized clinical trials, and tafamidis has been approved for the treatment of hereditary ATTR amyloidosis in more than 30 countries. In addition, gene therapies with small interfering RNAs and antisense oligonucleotides are promising strategies to ameliorate ATTR amyloidosis and currently in phase III clinical trials. Immunoglobulin light chain (AL) amyloidosis is a clonal, nonproliferative plasma cell disorder in which fragments of immunoglobulin light chain are deposited in tissues. Polyneuropathy, autonomic dysfunction, and carpal tunnel syndrome are common manifestations of AL amyloidosis. Recent progress of chemotherapies target for abnormal plasma cells, including stem cell transplant, melphalan + dexamethasone, bortezomib + dexamethasone (+ cyclophosphamide), lenalidomide + dexamethasone, and pomalidomide + dexamethasone, dramatically improved the prognosis of AL amyloidosis patients. At present, effective disease-modifying therapies are available in almost all systemic amyloidoses, and therefore, early diagnosis and therapy are critical.
《Curriculum Vitae》
Education:
1998 Ph.D. Shinshu University Graduate School of Medicine 1991 M.D. Shinshu University School of Medicine Professional Training and Employment:
2013-present Associate Professor, Department of Medicine (Neurology and Rheumatology), Shinshu University
2006-2013 Associate Professor, Division of Clinical and Molecular Genetics, Shinshu University
2005-2006 Junior Associate Professor, Department of Medicine (Neurology and Rheumatology), Shinshu University
2004-2005 Assistant Professor, Department of Medicine (Neurology and Rheumatology), Shinshu University
2002-2004 Postdoctoral fellow, the Scripps Research Institute, La Jolla, CA, USA 2000-2002 Assistant Professor, Department of Medicine (Neurology and
Rheumatology), Shinshu University
1999-2000 Visiting Scholar, Department of Molecular Biology, Tokyo Institute of Psychiatry, Tokyo
1993-1998 Senior Resident in Internal Medicine, Shinshu University 1991-1993 Junior Resident in Internal Medicine, Shinshu University
ホットトピックス HT-03：Cutting edge of metabolic/heredirary
Chairs：
Satoshi Kuwabara(Department of Neurology, Chiba University)
Haruki Koike(Department of Neurology, Nagoya University Graduate School of Medicine)
≪Objective≫
Our understanding on pathophysiology, genetics, and management of a variety of peripheral neuropathies has been increasing. The simpojium focuses on current status and perspective of pathophysiology and novel treatments of metabolic and hereditary neuropathies, such as amyloid neuropathy, POEMS syndrome, drug-induced neuropathy, and Charcot-Marie-Tooth disease. Paricularly neurologists should be more intensively involved in the diagnosis and management of chemptherapy-induced neuropathy.
HT-03-1
Cutting-edge therapies for amyloid neuropathy
Department of Medicine (Neurology & Rheumatology), Shinshu University School of Medicine
○Yoshiki Sekijima
The amyloidoses are a large group of postsecretory protein misfolding and deposition diseases. The misfolding and misassembly of 31 secreted human proteins are linked to amyloidosis.Transthyretin (TTR), a homotetrameric protein, is a representative amyloidogenic protein in humans. Rate-limiting tetramer dissociation and rapid monomer misfolding and misassembly of variant TTR result in autosomal dominant hereditary ATTR amyloidosis (also called familial amyloid polyneuropathy). The current standard first-line treatment of herediaty ATTR amyloidosis is liver transplantation, which allows suppression of the main source of variant TTR. However, liver transplantation has a number of limitations. Furthermore, large numbers of patients are not good transplant candidates because of their age and/or advanced disease status. Recently, the clinical effects of TTR tetramer stabilizers, tafamidis and diflunisal, were demonstrated in randomized clinical trials, and tafamidis has been approved for the treatment of hereditary ATTR amyloidosis in more than 30 countries. In addition, gene therapies with small interfering RNAs and antisense oligonucleotides are promising strategies to ameliorate ATTR amyloidosis and currently in phase III clinical trials. Immunoglobulin light chain (AL) amyloidosis is a clonal, nonproliferative plasma cell disorder in which fragments of immunoglobulin light chain are deposited in tissues. Polyneuropathy, autonomic dysfunction, and carpal tunnel syndrome are common manifestations of AL amyloidosis. Recent progress of chemotherapies target for abnormal plasma cells, including stem cell transplant, melphalan + dexamethasone, bortezomib + dexamethasone (+ cyclophosphamide), lenalidomide + dexamethasone, and pomalidomide + dexamethasone, dramatically improved the prognosis of AL amyloidosis patients. At present, effective disease-modifying therapies are available in almost all systemic amyloidoses, and therefore, early diagnosis and therapy are critical.
《Curriculum Vitae》
Education:
1998 Ph.D. Shinshu University Graduate School of Medicine 1991 M.D. Shinshu University School of Medicine Professional Training and Employment:
2013-present Associate Professor, Department of Medicine (Neurology and Rheumatology), Shinshu University
2006-2013 Associate Professor, Division of Clinical and Molecular Genetics, Shinshu University
2005-2006 Junior Associate Professor, Department of Medicine (Neurology and Rheumatology), Shinshu University
2004-2005 Assistant Professor, Department of Medicine (Neurology and Rheumatology), Shinshu University
2002-2004 Postdoctoral fellow, the Scripps Research Institute, La Jolla, CA, USA 2000-2002 Assistant Professor, Department of Medicine (Neurology and
Rheumatology), Shinshu University
1999-2000 Visiting Scholar, Department of Molecular Biology, Tokyo Institute of Psychiatry, Tokyo
1993-1998 Senior Resident in Internal Medicine, Shinshu University 1991-1993 Junior Resident in Internal Medicine, Shinshu University
ホットトピックス HT-03：Cutting edge of metabolic/heredirary neuropathies
5月18日（水） 9：50～11：50 第5会場(神戸国際展示場2号館2F 2A会議室)
184 -ホッ
トト ピッ クス
HT-03-2
Therapeutic strategy for Charcot-Marie-Tooth disease
North Medical Center, Kyoto Prefectural University of Medicine
○Masanori Nakagawa
More than 70 causative genes for Charcot-Marie-Tooth disease (CMT) have been identified so far. However, clinical evidence to treat and improve CMT patient care has been poorly developed. To date, there is no approved pharmacologic treatment for any form of CMT.
However, some clinical or preclinical trials for CMT1A have been undertaken, for example trials with high dose ascorbic acid (no efficacy by RCT), Neurotrophin-3 (AAV1-NT-3gene therapy), PXT3003 (a combination of baclofen, naltrexone and sorbitol), and neuregulin-1 (enhancement of PI3K-Akt signaling) . Also potential Pan Assay Interference Compounds (PAINS) which suppress PMP22 expression are testing by quantitative high-throughput screen (qHTS). Curcumin (popular Indian curry spice turmeric) may have some effects in CMT patients with MPZ or PMP22 mutation through decrease of ER stress.
Gene therapy for CMT1X，CMT2F and Giant axonal neuropathy using animal model or culture cells have been reported with some interesting results. Stem cell research, for example iPS cells derived from patients with CMT2A or CMT2E, is being conducted to clarify the mechanism of CMT and find therapeutic clues. The development of new surrogate markers for clinical trials is also needed. Under close collaboration among neurologist, orthopedists, rehabilitation researchers, pediatricians, and CMT patient group, CMT Patient Registry (CMTPR) system for expecting clinical trial, CMT education system (CMT practical manual, CMT public seminar, and consultation activity), clinical application of robotics (HAL-HN01 which was approved by PMDA), practical manual for surgical therapy, rehabilitation, Ankle-foot orthoses, and pain control are developing in Japan supported by AMED.
《Curriculum Vitae》
1978 Graduated from Kagoshima University Faculty of Medicine 1978-1979 Residency, Kagoshima University Faculty of Medicine, Internal
Medicine
1982-1984 Fellowship, Columbia University, Department of Neurology 1993-2002 Lecturer, Kagoshima University Faculty of Medicine, Internal
Medicine y
2002-2013 Professor and chairman, Department of Neurology, Kyoto Prefectural University of Medicine,
2014- present Director of North Medical Center, Kyoto Prefectural University of Medicine
2015- present Vice-President of Kyoto Prefectural University of Medicine RESEARCH INTEREST:
The molecular mechanisms for neurological diseases and Genetic counseling PROFESSIONAL MEMBERSHIPS:
The Japanese Society of Neurology, The Japanese Society of Internal Medicine, The Japan Society of Human Genetics, Japanese Society for Neuroinfectious Diseases, The Japan Stroke Society, Japanese Peripheral Nerve Society, The Japanese Association of Rehabilitation Medicine and more societies
HT-03-3
Current therapeutic strategies for POEMS syndrome
Department of Neurology, Graduate School of Medicine, Chiba University
○Sonoko Misawa
POEMS syndrome is a paraneoplastic disorder related to plasma cell dyscrasia. and the prognosis was miserable in 1980s. New therapeutic interventions applied from those for other plasma cell disorders, such as multiple myeloma, have substantially improved the prognosis of POEMS syndrome since 2000s. The current first line therapy is high-dose chemotherapy with autologous stem cell transplantation, whereas patients who are not eligible for transplantation are treated with immunomodulatory drugs. Moreover, there will be increasing numbers of therapeutic choices for myeloma, e.g. the next generation of immunomodulatory drugs or molecular target drugs, in the near future and they would be effective for POEMS syndrome. Treatment for POEMS syndrome is entering a new era. Well-designed prospective clinical trials are essential for further improvement of the prognosis.
We have addressed the development of POEMS syndrome treatments since 2003 and completed the first randomized controlled trial. This presentation will introduce our efforts for improvement of the prognosis of the rare and severe disease.
《Curriculum Vitae》
Position: Lecturer of Department of Neurology, Graduate School of Medicine, Chiba University, Japan
Professional Experience:
April 2006 to November 2008, Postdoctoral Fellow, Department of Neurology, Graduate School of Medicine, Chiba University From December 2008, Assistant Professor of Department of Neurology, Graduate School of Medicine, Chiba University From July 2014, Lecturer of Department of Neurology, Graduate School of Medicine, Chiba University
Research field: Clinical neurophysiology, peripheral neuropathy Awards: Brazier Award, ICCN 2006; Young investigator award, ICCN 2010…etc.
ホットトピックス HT-03：Cutting edge of metabolic/heredirary neuropathies
5月18日（水） 9：50～11：50 第5会場(神戸国際展示場2号館2F 2A会議室)
185
-ホッ トト ピッ クス
HT-03-4
Chemotherapy-induced Peripheral Neuropathy: From Pathophysiology to Neuroprotection
Brain and Mind Centre, University of Sydney, Australia
○Susanna B. Park
The peripheral nervous system is highly susceptible to the development of toxicity. Chemotherapy-induced peripheral neurotoxicity (CIPN) is a serious consequence of cancer treatment, which occurs with some of the most commonly used chemotherapies, including platinum agents, taxanes and vinca alkaloids. CIPN may lead to difficulties with fine motor skills and walking, leading to long-lasting functional impairment. There are no established neuroprotective or treatment options and a lack of sensitive assessment methods. Conventional nerve conduction studies may only identify nerve damage once significant axonal damage has occurred. Over the past 20 years, axonal excitability techniques have been developed to identify aberrant membrane and ion channel function in vivo. These techniques have been successfully utilised in the clinical research setting to provide insights into pathophysiology in a number of peripheral nerve disorders. Nerve excitability techniques have now been established as a tool to examine the development and severity of CIPN, to assess both acute neurotoxicity arising immediately following infusion and the development of cumulative neuropathy. Significant abnormalities developed during early treatment in oxaliplatin-treated patients, prior to any reduction in sensory amplitudes, suggesting that excitability parameters may provide a sensitive biomarker. The development of sensitive assessment tools is a necessary step towards the identification of successful neuroprotective strategies.
《Curriculum Vitae》
Dr Susanna Park is Senior Lecturer in Physiology at the Brain and Mind Centre, University of Sydney. Dr Park has expertise in clinical application of nerve excitability techniques, with research involvement in toxic, metabolic, inflammatory and inherited neuropathies and motor neuron diseases. She obtained her PhD from the University of New South Wales in ‘The pathogenesis of chemotherapy-induced peripheral neuropathy’，followed by a postdoctoral fellowship at the Institute of Neurology, University College London as an RG Menzies/NHMRC Overseas Biomedical Fellow. Since her return to Australia, Dr Park has been awarded research funding in the areas of chemotherapy-induced peripheral neuropathy, inflammatory neuropathies and motor neuron disorders.
ホットトピックス HT-03：Cutting edge of metabolic/heredirary neuropathies
5月18日（水） 9：50～11：50 第5会場(神戸国際展示場2号館2F 2A会議室)
ホッ トト ピッ クス
HT-03-4
Chemotherapy-induced Peripheral Neuropathy: From Pathophysiology to Neuroprotection
Brain and Mind Centre, University of Sydney, Australia
○Susanna B. Park
The peripheral nervous system is highly susceptible to the development of toxicity. Chemotherapy-induced peripheral neurotoxicity (CIPN) is a serious consequence of cancer treatment, which occurs with some of the most commonly used chemotherapies, including platinum agents, taxanes and vinca alkaloids. CIPN may lead to difficulties with fine motor skills and walking, leading to long-lasting functional impairment. There are no established neuroprotective or treatment options and a lack of sensitive assessment methods. Conventional nerve conduction studies may only identify nerve damage once significant axonal damage has occurred. Over the past 20 years, axonal excitability techniques have been developed to identify aberrant membrane and ion channel function in vivo. These techniques have been successfully utilised in the clinical research setting to provide insights into pathophysiology in a number of peripheral nerve disorders. Nerve excitability techniques have now been established as a tool to examine the development and severity of CIPN, to assess both acute neurotoxicity arising immediately following infusion and the development of cumulative neuropathy. Significant abnormalities developed during early treatment in oxaliplatin-treated patients, prior to any reduction in sensory amplitudes, suggesting that excitability parameters may provide a sensitive biomarker. The development of sensitive assessment tools is a necessary step towards the identification of successful neuroprotective strategies.
《Curriculum Vitae》
Dr Susanna Park is Senior Lecturer in Physiology at the Brain and Mind Centre, University of Sydney. Dr Park has expertise in clinical application of nerve excitability techniques, with research involvement in toxic, metabolic, inflammatory and inherited neuropathies and motor neuron diseases. She obtained her PhD from the University of New South Wales in ‘The pathogenesis of chemotherapy-induced peripheral neuropathy’，followed by a postdoctoral fellowship at the Institute of Neurology, University College London as an RG Menzies/NHMRC Overseas Biomedical Fellow. Since her return to Australia, Dr Park has been awarded research funding in the areas of chemotherapy-induced peripheral neuropathy, inflammatory neuropathies and motor neuron disorders.
ホットトピックス HT-03：Cutting edge of metabolic/heredirary neuropathies
5月18日（水） 9：50～11：50 第5会場(神戸国際展示場2号館2F 2A会議室)
186 -ホッ
トト ピッ クス
座長：
永井義隆(大阪大学大学院医学研究科 神経難病認知 症探索治療学/国立精神・神経医療研究セン ター 神経研究所 疾病研究第四部)
山中宏二(名古屋大学環境医学研究所 病態神経科学 分野)
≪ねらい≫
神経疾患の病態解明，治療法開発を目指して様々な動物モ デルが開発され，これらの貢献により疾患研究が大きく進ん できた．従来から汎用されているマウス，ラットなどの哺乳 類に加え，近年はより低コスト，短時間でのハイスループッ ト解析に適している線虫，ショウジョウバエ，小型魚類など の疾患モデルを用いた網羅的な解析により，多くの研究成果 がもたらされた．さらに最近我が国において，霊長類である マーモセットの遺伝子改変技術が開発され，よりヒトに近い 疾患モデルを用いた研究を行うことができる体制が整った．
一方で，CRISPR/Cas9システムなどの最新のゲノム編集技 術を用いた迅速・簡便なノックアウト動物の作製技術が開発 され，注目を浴びている．本シンポジウムでは，線虫から霊