アミロイドーシス

テーマ1：アミロイドーシスの病態解明と新規治療法の確立

アミロドーシスは，線維状の不溶性のタンパク質が臓器に沈着することにより惹起される病気で，代表的な疾患にアルツハイマー病や遺伝性ATTRアミロイドーシス（家族性アミロイドポリニューロパチー，FAP）があります．私たちは特に，FAPの病態解明と治療法の開発に取り組んでおり，これまでにTTR遺伝子変異に起因するTTR四量体蛋白構造の不安定化がFAPの根本的な原因であること見いだし（Cell, 2005），TTR四量体を安定化する薬剤を用いた新規治療法を開発し（US patent No. 7,214,696; JAMA, 2013），実用化しました．また，siRNAを用いた遺伝子治療（N Engl J Med, 2018）など多くの国際治験にも携わっています．さらに私たちが開発した私たちが開発したTTR四量体安定化薬は，高齢者における心不全や手根管症候群の主要な原因となっている野生型ATTRアミロイドーシス（老人性全身性アミロイドーシス）に対しても有効であることが最近証明されました．また，アルツハイマー病の国際的な臨床研究であるDIAN研究にも参加し，common diseaseであるアミロイドーシスの病態解明と新規治療法に取り組んでいます．

代表的な業績

  1. Sekijima Y, Wiseman LR, Matteson J, Hammarström P, Miller SR, Sawkar AR, Balch WE, Kelly JW. The biological and chemical basis for tissue selective amyloid disease. Cell 121: 73-85, 2005
  2. Berk JL, Suhr OB, Obici L, Sekijima Y, Zeldenrust SR, Yamashita T, Heneghan MA, Gorevic PD, Litchy WJ, Wiesman JF, Nordh E, Corato M, Lozza A, Cortese A, Robinson-Papp J, Colton T, Rybin DV, Bisbee AB, Ando Y, Ikeda S, Seldin DC, Merlini G, Skinner M, Kelly JW, Dyck PJ; Diflunisal Trial Consortium. Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA 310: 2658-2667, 2013
  3. Sekijima Y. Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments. J Neurol Neurosurg Psychiatry 86:1036-1043, 2015
  4. Nakagawa M, Sekijima Y, Yazaki M, Tojo K, Yoshinaga T, Doden T, Koyama J, Yanagisawa S, Ikeda SI. Carpal tunnel syndrome: a common initial symptom of systemic wild-type ATTR (ATTRwt) amyloidosis. Amyloid 23: 58-63, 2016
  5. Sekijima Y, Yazaki M, Ueda M, Koike H, Yamada M, Ando Y. First nationwide survey on systemic wild-type ATTR amyloidosis in Japan. Amyloid 25: 8-10, 2018
  6. Adams D, Gonzalez-Duarte A, O'Riordan WD, Yang CC, Ueda M, Kristen AV, Tournev I, Schmidt HH, Coelho T, Berk JL, Lin KP, Vita G, Attarian S, Planté-Bordeneuve V, Mezei MM, Campistol JM, Buades J, Brannagan TH 3rd, Kim BJ, Oh J, Parman Y, Sekijima Y, Hawkins PN, Solomon SD, Polydefkis M, Dyck PJ, Gandhi PJ, Goyal S, Chen J, Strahs AL, Nochur SV, Sweetser MT, Garg PP, Vaishnaw AK, Gollob JA, Suhr OB. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N Engl J Med 379: 11-21, 2018
  7. Takahashi Y, Ohashi N, Takasone K, Yoshinaga T, Yazaki M, Roberts M, Glidden PF, Sekijima Y. CSF/plasma levels, transthyretin stabilisation and safety of multiple doses of tolcapone in subjects with hereditary ATTR amyloidosis. Amyloid 29:190-196, 2022
  8. Adams D, Tournev IL, Taylor MS, Coelho T, Planté-Bordeneuve V, Berk JL, González-Duarte A, Gillmore JD, Low SC, Sekijima Y, Obici L, Chen C, Badri P, Arum SM, Vest J, Polydefkis M; HELIOS-A Collaborators. Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial. Amyloid 30:18-26, 2023
  9. Maurer MS, Kale P, Fontana M, Berk JL, Grogan M, Gustafsson F, Hung RR, Gottlieb RL, Damy T, González-Duarte A, Sarswat N, Sekijima Y, Tahara N, Taylor MS, Kubanek M, Donal E, Palecek T, Tsujita K, Tang WHW, Yu WC, Obici L, Simões M, Fernandes F, Poulsen SH, Diemberger I, Perfetto F, Solomon SD, Di Carli M, Badri P, White MT, Chen J, Yureneva E, Sweetser MT, Jay PY, Garg PP, Vest J, Gillmore JD; APOLLO-B Trial Investigators. Patisiran Treatment in Patients with Transthyretin Cardiac Amyloidosis. N Engl J Med 389(17):1553-1565, 2023
  10. Adams D, Sekijima Y, Conceição I, Waddington-Cruz M, Polydefkis M, Echaniz-Laguna A, Reilly MM. Hereditary transthyretin amyloid neuropathies: advances in pathophysiology, biomarkers, and treatment. Lancet Neurol 22(11): 1061-1074, 2023
  11. Kelly JW, Sekijima Y. Compositions and methods for stabilizing transthyretin and inhibiting transthyretin misfolding. US patent No. 7,214,696

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テーマ2：微量蛋白解析やアミロイドイメージングを用いたアミロイドーシスの新規診断法の開発

これまでアミロイド蛋白の精製・解析には多くの時間がかかり，また解析途中の蛋白のロスが多いため，小さな組織材料では解析が困難でした．私たちの研究グループでは，レーザーマイクロダイセクッション（LMD）とタンデム質量分析（LC/MS/MS）を用いた最新の解析技術で微量組織からのアミロイド解析を行っており，この方法を用いて世界初の野生型ACysアミロイドーシスや，日本初のAFibアミロイドーシス，AApoAIアミロイドーシスの診断に成功しました．また，LMD-LC/MS/MSをアミロイドーシスの病態解析にも応用しています．
さらに，非侵襲的なアミロイドーシスの診断方法として，アルツハイマー病研究に用いられているPiB-PETを様々な全身性アミロイドーシスに応用し，全身のアミロイド沈着を評価できることを明らかにしました．今後様々なアミロイドイメージングの実用化を目指していきます．

代表的な業績

  1. Sekijima Y, Yazaki M, Oguchi K, Ezawa N, Yoshinaga T, Yamada M, Yahikozawa H, Watanabe M, Kametani F, Ikeda SI. Cerebral amyloid angiopathy in post-transplant patients with hereditary ATTR amyloidosis. Neurology 87: 773-781, 2016
  2. Yoshinaga T, Yazaki M, Sekijima Y, Kametani F, Miyashita K, Hachiya N, Tanaka T, Kokudo N, Higuchi K, Ikeda SI. The pathological and biochemical identification of possibleseed-lesions of transmitted transthyretin amyloidosis after domino liver transplantation. J Path: Clin Res 2: 72-79, 2016
  3. Yoshinaga T, Yazaki M, Kametani F, Sekijima Y, Iesato Y, Miyahara T, Tsuchiya-Suzuki A, Sano K, Higuchi K, Ikeda SI. Marked biochemical difference in amyloid proportion between intra- and extraocular tissues in a liver-transplanted patient with hereditary ATTR amyloidosis. Amyloid 24: 17-23, 2017
  4. Ezawa N, Katoh N, Oguchi K, Yoshinaga T, Yazaki M, Sekijima Y. Visualisation of multiple organ amyloid involvement in systemic amyloidosis using 11C-PiB-PET imaging. Eur J Nucl Med Mol Imaging 45: 452-461, 2018
  5. Yazaki M, Yoshinaga T, Sekijima Y, Kametani F, Okumura F. Hereditary fibrinogen A-chain amyloidosis in Asia: Clinical and molecular characteristics. Int. J. Mol. Sci 19: pii: E320, 2018
  6. Takasone K, Katoh N, Takahashi Y, Abe R, Ezawa N, Yoshinaga T, Yanagisawa S, Yazaki M, Oguchi K, Koyama J, Sekijima Y. Non-invasive detection and differentiation of cardiac amyloidosis using 99mTc-pyrophosphate scintigraphy and 11C-Pittsburgh compound B PET imaging. Amyloid 27:266-274, 2020
  7. Ichimata S, Katoh N, Abe R, Yoshinaga T, Kametani F, Yazaki M, Uehara T, Sekijima Y.　A case of novel amyloidosis: glucagon-derived amyloid deposition associated with pancreatic neuroendocrine tumour. Amyloid 28: 72-73, 2021.
  8. Yanagisawa S, Takahashi Y, Sasaki J, Takasone K, Yoshie K, Koyama J, Katoh N, Yazaki M, Kuwahara K, Fujinaga Y, Sekijima Y. Absolute quantitative analysis of cardiac amyloidosis using SPECT/CT with 99mTc-pyrophosphate. Amyloid 28(3):213-214, 2021
  9. Nakagawa M, Yazaki M, Kametani F, Katoh N, Yoshinaga T, Higuchi K, Sekijima Y. Development of diagnostic antibodies against immunoglobulin heavy chain variable region for heavy chain amyloidosis (AH amyloidosis). Pathol Int 71(4):245-254, 2021
  10. Ichimata S, Katoh N, Abe R, Yoshinaga T, Kametani F, Yazaki M, Kusama Y, Sano K, Uehara T, Sekijima Y. Somatostatin-derived amyloid deposition associated with duodenal neuroendocrine tumour (NET): a report of novel localised amyloidosis associated with NET. Amyloid 29:64-65. 2022
  11. Oguchi K, Katoh N, Mochizuki Y, Takahashi Y, Ueno A, Takasone K, Sekijima Y. Reduction of cardiac AL amyloid deposition after complete response visualised by PiB-PET imaging. Amyloid 30: 138-139, 2023
  12. Takahashi Y, Oguchi K, Mochizuki Y, Takasone K, Ezawa N, Matsushima A, Katoh N, Yazaki M, Sekijima Y. Distribution and progression of cerebral amyloid angiopathy in early-onset V30M (p.V50M) hereditary ATTR amyloidosis. Amyloid 30:109-118, 2023

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