School of Medicine, Department of Internal Medicine (Neurology) Department of Neurology, Keio University School of Medicine (Shinanomachi)



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Profile 【 Display / hide

  • - Japanese Society of Neurology
    District Representative
    - Japanese Society of Internal Medicine
    - Japanese Society of Neuroimmunology
    - Japanese Society of Neurological Therapeutics
    - Japanese Society for Neuroinfectious Diseases
    - Japan Multiple Sclerosis Network
    - Pan-Asian Congress for Treatment and Research in Multiple Sclerosis (PACTRIMS)
    Central organizing committee member

Message from the Faculty Member 【 Display / hide

  • We aim to develop actual therapeutics by every conceivable means – from advancement of translational research to home care medicine – to improve the quality of life of patients suffering from various neurological diseases.

Other Affiliation 【 Display / hide

  • Keio University Global Research Institute (KGRI), Deputy Director

Career 【 Display / hide

  • 2003.04

    慶應義塾大学, COEプログラム(生命科学), 研究員

  • 2004.04

    独立行政法人日本学術振興会, 特別研究員(DC1)

  • 2007.04

    独立行政法人日本学術振興会, 特別研究員(PD)

  • 2008.12

    慶應義塾大学, 医学部総合医科学研究センター, 特任講師

  • 2013.04

    慶應義塾大学, 医学部内科学教室(神経), 助教

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Academic Background 【 Display / hide

  • 2003.03

    Keio University, School of Medicine

    University, Graduated

  • 2007.03

    Keio University, Graduate School, Division of Medicine, 生理系専攻

    Graduate School, Completed, Doctoral course

Academic Degrees 【 Display / hide

  • 博士(医学), Keio University, Coursework, 2007.03

Licenses and Qualifications 【 Display / hide

  • Medical license, 2003.05

  • Certified occupational physician, 2011.09

  • Board certified member of the Japanese Society of Internal Medicine, 2013.09

  • Board certified neurologist, 2014.07

  • Fellow of the Japanese Society of Internal Medicine (FJSIM), 2019.12


Research Areas 【 Display / hide

  • Neurology

Research Keywords 【 Display / hide

  • Oligodendrocyte

  • Multiple sclerosis

  • Neuroimmunology

  • Neurology

  • Neuromyelitis optica spectrum disorder

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Research Themes 【 Display / hide

  • 神経治療学の拠点形成, 


  • 多発性硬化症の臨床研究, 


  • 中枢神経系髄鞘再生療法の開発, 



Papers 【 Display / hide

  • Cytometric cell-based assays for anti-striational antibodies in myasthenia gravis with myositis and/or myocarditis

    Kufukihara K., Watanabe Y., Inagaki T., Takamatsu K., Nakane S., Nakahara J., Ando Y., Suzuki S.

    Scientific Reports (Scientific Reports)  9 ( 1 )  2019.12

     View Summary

    © 2019, The Author(s). The purposes of the present study were to identify anti-striational antibodies in myasthenia gravis (MG) patients with myositis and/or myocarditis using a combination of cell-based assays and flow cytometry (cytometric cell-based assays) and to describe the main clinical implications. Among 2,609 stored samples collected from all over Japan between 2003 and 2016, we had serum samples from 30 MG patients with myositis and/or myocarditis. Cytometric cell-based assays with titin, ryanodine receptor, and voltage-gated Kv1.4 were performed. Autoantibodies were determined by differences in phycoerythin fluorescence between the 293F cells and titin-transfected cells. MG patients with myositis and/or myocarditis as well as late-onset and thymoma-associated MG had anti-titin, anti-ryanodine receptor, and anti-Kv1.4 antibodies. In contrast, patients with early-onset MG, those with other myopathies and healthy controls did not have anti-titin or anti-Kv1.4 antibodies with some exceptions, but they possessed anti-ryanodine receptor antibodies. Thirty MG patients with myositis and/or myocarditis showed a severe generalized form, and 21 of them had thymoma. Anti-titin and anti-Kv1.4 antibodies were found in 28 (93%) and 15 (50%) patients, respectively, and all patients had at least one of these antibodies. Cytometric cell-based assays thus demonstrated that anti-striational antibodies are biomarkers of MG with myositis and/or myocarditis.

  • Ropinirole hydrochloride remedy for amyotrophic lateral sclerosis – Protocol for a randomized, double-blind, placebo-controlled, single-center, and open-label continuation phase I/IIa clinical trial (ROPALS trial)

    Morimoto S., Takahashi S., Fukushima K., Saya H., Suzuki N., Aoki M., Okano H., Nakahara J.

    Regenerative Therapy (Regenerative Therapy)  11   143 - 166 2019.12

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    © 2019 The Japanese Society for Regenerative Medicine Introduction: Amyotrophic lateral sclerosis (ALS) is an intractable and incurable neurological disease. It is a progressive disease characterized by muscle atrophy and weakness caused by selective vulnerability of upper and lower motor neurons. In disease research, it has been common to use mouse models carrying mutations in responsible genes for familial ALS as pathological models of ALS. However, there is no model that has reproduced the actual conditions of human spinal cord pathology. Thus, we developed a method of producing human spinal motor neurons using human induced pluripotent stem cells (iPSCs) and an innovative experimental technique for drug screening. As a result, ropinirole hydrochloride was eventually discovered after considering such results as its preferable transitivity in the brain and tolerability, including possible adverse reactions. Therefore, we explore the safety, tolerability and efficacy of ropinirole hydrochloride as an ALS treatment in this clinical trial. Methods: The ROPALS trial is a single-center double-blind randomized parallel group-controlled trial of the safety, tolerability, and efficacy of the ropinirole hydrochloride extended-release tablet (Requip CR) at 2- to 16-mg doses in patients with ALS. Twenty patients will be recruited for the active drug group (fifteen patients) and placebo group (five patients). All patients will be able to receive the standard ALS treatment of riluzole if not changed the dosage during this trial. The primary outcome will be safety and tolerability at 24 weeks, defined from the date of randomization. Secondary outcome will be the efficacy, including any change in the ALS Functional Rating Scale-Revised (ALSFRS-R), change in the Combined Assessment of Function and Survival (CAFS), and the composite endpoint as a sum of Z-transformed scores on various clinical items. Notably, we will perform an explorative search for a drug effect evaluation using the patient-derived iPSCs to prove this trial concept. Eligible patients will have El Escorial Possible, clinically possible and laboratory-supported, clinically probable, or clinically definite amyotrophic lateral sclerosis with disease duration less than 60 months (inclusive), an ALSFRS-R score ≥2 points on all items and age from 20 to 80 years. Conclusion: Patient recruitment began in December 2018 and the last patient is expected to complete the trial protocol in November 2020. Trial registration: Current controlled trials UMIN000034954 and JMA-IIA00397 Protocol version: version 1.6 (Date; 5/Apr/2019).

  • Ropinirole Hydrochloride for ALS

    Takahashi S., Morimoto S., Fukushima K., Nakahara J., Okano H.

    Brain and nerve = Shinkei kenkyu no shinpo (Brain and nerve = Shinkei kenkyu no shinpo)  71 ( 11 ) 1279 - 1288 2019.11

    ISSN  18816096

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    Our laboratory previously established spinal motor neurons (MN) from induced-pluripotent stem cells (iPSCs) prepared from both sporadic and familial ALS patients, and successfully recapitulated disease-specific pathophysiological processes. We next searched for effective drugs capable of slowing the progression of ALS using a drug library of 1232 existing compounds and discovered that ropinirole hydrochloride prevented MN death. In December 2018, we started an investigator-initiated clinical trial testing ropinirole hydrochloride extended-release tablets in ALS patients. This is an on-going phase I/IIa randomized, double-blind, placebo-controlled, single-center, open-label continuation clinical trial (UMIN000034954). The primary aim is to assess the safety and tolerability of ropinirole hydrochloride in patients with ALS. We will also perform an efficacy evaluation using patient-derived iPSCs/MN. Major inclusion criteria were as follows: 1) 'clinically possible and laboratory-supported ALS', 'clinically probable ALS' or 'clinically definite ALS', according to the criteria for the diagnosis of ALS (El Escorial revised) and within 60 months after disease onset; 2) change in ALSFRS-R score of -2 to -5 points during the 12-week run-in period. Finally, 15 patients will be assigned to the active drug and 5 patients to the placebo. Our trial will be a touchstone trial for iPSC-based drug development strategies.

  • Inflammatory myopathy associated with PD-1 inhibitors

    Seki M., Uruha A., Ohnuki Y., Kamada S., Noda T., Onda A., Ohira M., Isami A., Hiramatsu S., Hibino M., Nakane S., Noda S., Yutani S., Hanazono A., Yaguchi H., Takao M., Shiina T., Katsuno M., Nakahara J., Matsubara S., Nishino I., Suzuki S.

    Journal of Autoimmunity (Journal of Autoimmunity)  100   105 - 113 2019.06

    ISSN  08968411

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    © 2019 Elsevier Ltd Objective: To characterize the inflammatory myopathy associated with programmed cell death 1 inhibitors (PD-1 myopathy). Methods: We studied 19 Japanese patients with PD-1 myopathy (13 men and 6 women, mean age 70 years), who were referred to Keio University. As control groups, we used 68 patients with anti-signal recognition particle antibodies, 51 patients with anti-aminoacyl transfer RNA synthetase antibodies and 460 healthy subjects. Results: In regard to muscle-disease severity, 10 patients showed a mild form of disease and 9 patients showed a severe form. Non-small cell lung cancer was the most common underlying cancer. PD-1 inhibitor consisted of 11 nivolumab and 8 pembrolizumab. PD-1 myopathy occurred 29 days on average after the first administration of PD-1 inhibitor. The initial manifestation of muscle weakness was ptosis in 10 patients, 15 patients had ptosis, 13 diplopia, 8 facial muscle weakness, 10 bulbar symptoms, 13 limb weakness, 14 neck weakness, 4 cardiac involvement, 6 respiratory involvement and 16 myalgia. Ocular, facial, cardiac and respiratory involvement and myalgia were more frequently observed than controls. Serum creatine kinase was increased to 5247 IU/L on average. Autoantibodies related to inflammatory myopathy were negative, while anti-striational antibodies were found in 13 (68%)patients. HLA-C*12:02 alleles were more frequently detected than healthy controls. Muscle pathology was characterized by multifocal necrotic myofibers with endomysial inflammation and expression of MHC class I. Immunosuppressive therapy with corticosteroids was generally effective for muscle weakness. Conclusions: Based on our clinical, histological and immunological findings, PD-1 myopathy is a discrete subset of inflammatory myopathy.

  • Three cases of non-carryover fingolimod-PML: Is the risk in Japan increased?

    Nakahara J., Tomaske L., Kume K., Takata T., Kamada M., Deguchi K., Kufukihara K., Schneider R., Gold R., Ayzenberg I.

    Neurology: Neuroimmunology and NeuroInflammation (Neurology: Neuroimmunology and NeuroInflammation)  6 ( 3 )  2019.05

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    © 2019 American Academy of Neurology. ObjectiveTo report the course of 3 recent Japanese and European cases of fingolimod-associated progressive multifocal leukoencephalopathy (PML) and to analyze its risk factors and increased incidence in Japan.MethodsCase series and literature review.ResultsFingolimod-associated PML may cause both supratentorial and infratentorial lesions and a pronounced disability. Diagnosis can be challenging because PML lesions (especially infratentorial) can be initially misdiagnosed as extensive MS lesions. Immune reconstitution inflammatory syndrome (IRIS) develops a few weeks after fingolimod discontinuation and is usually mild. Age factor and therapy duration seem to be relevant because most reported patients were older than 45 years and were treated with fingolimod for more than 3 years. Combined IgG/IgM deficiency has been identified as a possible further predisposing condition in 1 case. Another patient developed an endogenous fungal skin infection, as a sign of generally compromised cellular immune response, shortly before PML. None of the reported patients had lymphocyte counts below 200/l. Two of the 3 reported and 4 of the 21 (19%) registered fingolimod-PML cases occurred in Japan (estimated risk of 0.652 per 1,000 compared with 0.083 per 1.000 worldwide).ConclusionsThe risk of PML under fingolimod is low, but there are no reliable predictors. Despite a mild IRIS phase, it causes profound disability. Patients older than 45 years, especially with known comorbid immunodeficiencies or manifestation of other opportunistic infections, should be monitored more closely. Increased surveillance and identification of further risk factors are urgently needed in Japan.

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Papers, etc., Registered in KOARA 【 Display / hide

Research Projects of Competitive Funds, etc. 【 Display / hide

  • ミエリンマップ法を用いた多発性硬化症における髄鞘病理の画像解析


    MEXT,JSPS, Grant-in-Aid for Scientific Research, 中原 仁, Grant-in-Aid for Scientific Research (C), Principal Investigator

  • 髄鞘の可視化技術による多発性硬化症の病型分類に関する研究


    文部科学省, Grant-in-Aid for Scientific Research, 中原仁, Principal Investigator

  • 髄鞘を標的とした神経変性疾患・脊髄損傷に対する新規治療戦略に関する研究


    文部科学省, Grant-in-Aid for Scientific Research, 中原仁, Principal Investigator

  • アストロサイトによるin vivoケトン体生合成機構の解明


    文部科学省, Grant-in-Aid for Scientific Research, 中原仁, Principal Investigator

  • 内在性オリゴデンドロサイト前駆細胞の分化誘導を基盤とする中枢神経系髄鞘再生医薬の開発


    独立行政法人医薬基盤研究所, -, 中原仁, Principal Investigator

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Intellectual Property Rights, etc. 【 Display / hide

  • Drug delivery system toward demyelinating lesion and biochemical marker of demyelinating lesions

    Application No.: 8252540  2012.08 

    Registration No.: 8252540  2012.08

    Patent, Joint

  • Medicinal compositions containing Fc receptor γ chain activator

    Application No.: 7901678  2011.03 

    Registration No.: 7901678  2011.03

    Patent, Joint

  • Fc受容体γ鎖活性化物質を含有する医薬組成物

    Application No.: 4214249  2008.11 

    Registration No.: 4214249  2008.11

    Patent, Joint

Awards 【 Display / hide

  • Best Presentation Award

    2017, Sendai Conference

  • MSJ-PACTRIMS investigator award

    2014, Pan-Asian Committee for Treatment and Research in Multiple Sclerosis (PACTRIMS)

  • 優秀指導教官賞

    2014, 日本内科学会

  • MSJ-PACTRIMS Investigator Award

    2014, PACTRIMS

  • 優秀指導教官賞

    2014, 内科学サミット2014

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Courses Taught 【 Display / hide











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