Development of effective evaluation method of bezafibrate for the fatty acid metabolism disorders using the iPS cells

• Project/Area Number: 16K21179
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics; Embryonic/Neonatal medicine
• Research Institution: Shimane University
• Principal Investigator: Yamada Kenji 島根大学, 学術研究院医学・看護学系, 助教 (70624930)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 脂肪酸代謝異常症 / ベザフィブラート / 代謝性ミオパチー / in vitro probe assay / 脂肪酸代謝能 / VLCAD欠損症 / CPT2欠損症 / FAOフラックス / 臨床治験 / in vitro prove assay / iPS細胞 / グルタル酸血症2型 / 酵素 / 脂肪酸代謝

Outline of Final Research Achievements

Although bezafibrate has been reported as a hopeful drug for fatty acid oxidation disorders (FAOD) in in vitro, a clinical trial showed no obvious efficacy. However, the clinical symptom was clearly improved in some patients. Therefore, I thought that its efficacy could not be completely denied, and the measurement of fatty acid oxidation capacity might be inappropriate.
In this study, I initially planned to develop and investigate a method for predicting the efficacy of bezafibrate using iPS cells. However, as a result, I found that modified conventional methods using fibroblasts derived from patients with FAOD, such as in vitro probe assay and fatty acid oxidation flux, can partially predict the efficacy of bezafibrate.

Academic Significance and Societal Importance of the Research Achievements

本研究結果はベザフィブラートの有効性を患者細胞を用いて予測するだけでなく、他の治療候補薬剤の有効性を検討することにも応用できる。本研究で発展させた脂肪酸代謝能の測定技術は一度に数～十数種類の薬剤を簡便に調べることが出来る。つまり、現時点ではベザフィブラートも含めて証明された治療薬のない脂肪酸代謝異常症への治療薬を探索する際に、患者由来の培養細胞を用いることで、安全に多数の薬剤を網羅的に検討できる。
さらに、脂肪酸代謝異常症だけでなく、ミトコンドリア病といった他の先天代謝異常症の治療薬の有効性を調べることにも応用できると思われる。

Research Products

• [Journal Article] Flavin adenine dinucleotide synthase deficiency due to FLAD1 mutation presenting as multiple acyl-CoA dehydrogenation deficiency-like disease: A case report (2019)
  • Author(s): Yamada Kenji、Ito Michinori、Kobayashi Hironori、Hasegawa Yuki、Fukuda Seiji、Yamaguchi Seiji、Taketani Takeshi
  • Journal Title: Brain and Development Volume: 41 Issue: 7 Pages: 638-642
  • DOI: 10.1016/j.braindev.2019.04.002
  • Peer Reviewed
• [Journal Article] A Japanese case of mitochondrial 3‐hydroxy‐3‐methylglutaryl‐CoA synthase deficiency who presented with severe metabolic acidosis and fatty liver without hypoglycemia (2019)
  • Author(s): Lee Tomoko、Takami Yuichi、Yamada Kenji、Kobayashi Hironori、Hasegawa Yuki、Sasai Hideo、Otsuka Hiroki、Takeshima Yasuhiro、Fukao Toshiyuki
  • Journal Title: JIMD Reports Volume: 48 Issue: 1 Pages: 19-25
  • DOI: 10.1002/jmd2.12051
  • Peer Reviewed / Open Access
• [Journal Article] Clinical course in a patient with myopathic VLCAD deficiency during pregnancy with an affected baby (2019)
  • Author(s): Yamada Kenji、Matsubara Keiichi、Matsubara Yuko、Watanabe Asami、Kawakami Sanae、Ochi Fumihiro、Kuwabara Kozue、Mushimoto Yuichi、Kobayashi Hironori、Hasegawa Yuki、Fukuda Seiji、Yamaguchi Seiji、Taketani Takeshi
  • Journal Title: JIMD Reports Volume: 49 Issue: 1 Pages: 17-20
  • DOI: 10.1002/jmd2.12061
  • Peer Reviewed / Open Access
• [Journal Article] Open-label clinical trial of bezafibrate treatment in patients with fatty acid oxidation disorders in Japan; 2nd report QOL survey (2019)
  • Author(s): Shiraishi H、Yamada K、Oki E、Ishige M、Fukao T、Hamada Y、Sakai N、Ochi F、Watanabe A、Kawakami S、Kuzume K、Watanabe K、Sameshima K、Nakamagoe K、Tamaoka A、Asahina N、Yokoshiki S、Miyakoshi T、Oba K、Isoe T、Hayashi H、Yamaguchi S、Sato N
  • Journal Title: Molecular Genetics and Metabolism Reports Volume: 20 Pages: 100496-100496
  • DOI: 10.1016/j.ymgmr.2019.100496
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Serum C14:1/C12:1 ratio is a useful marker for differentiating affected patients with very long-chain acyl-CoA dehydrogenase deficiency from heterozygous carriers (2019)
  • Author(s): Yamada Kenji、Osawa Yoshimitsu、Kobayashi Hironori、Hasegawa Yuki、Fukuda Seiji、Yamaguchi Seiji、Taketani Takeshi
  • Journal Title: Molecular Genetics and Metabolism Reports Volume: 21 Pages: 100535-100535
  • DOI: 10.1016/j.ymgmr.2019.100535
  • Peer Reviewed / Open Access
• [Journal Article] 【指定難病ペディア 2019】個別の指定難病 代謝・内分泌系 グルタル酸血症2型[指定難病250] (2019)
  • Author(s): 山田健治
  • Journal Title: 日本医師会雑誌 Volume: 148 Pages: 282-282
• [Journal Article] 【高血糖と低血糖-どう対応するか】低血糖の病態、診断と治療 脂肪酸代謝異常症(解説/特集) (2019)
  • Author(s): 山田健治
  • Journal Title: 小児内科 Volume: 51 Pages: 1026-1030
• [Journal Article] Two siblings with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency suffered from rhabdomyolysis after l -carnitine supplementation (2018)
  • Author(s): Watanabe Kenji、Yamada Kenji、Sameshima Koji、Yamaguchi Seiji
  • Journal Title: Molecular Genetics and Metabolism Reports Volume: 15 Pages: 121-123
  • DOI: 10.1016/j.ymgmr.2018.03.007
  • Peer Reviewed / Open Access
• [Journal Article] Diagnostic potential of stored dried blood spots for inborn errors of metabolism: a metabolic autopsy of medium-chain acyl-CoA dehydrogenase deficiency (2018)
  • Author(s): Noriyuki Kaku, Kenji Ihara, Yuichiro Hirata, Kenji Yamada, Sooyoung Lee, Hikaru Kanemasa, Yoshitomo Motomura, Haruhisa Baba, Tamami Tanaka, Yasunari Sakai, Yoshihiko Maehara, Shouichi Ohga
  • Journal Title: Journal of Clinical Pathology Volume: 71 Issue: 10 Pages: 885-889
  • DOI: 10.1136/jclinpath-2017-204962
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Diversity in the incidence and spectrum of organic acidemias, fatty acid oxidation disorders, and amino acid disorders in Asian countries: Selective screening vs. expanded newborn screening (2018)
  • Author(s): Shibata Naoaki、Hasegawa Yuki、Yamada Kenji、Kobayashi Hironori、Purevsuren Jamiyan、Yang Yanling、Dung Vu Chi、Khanh Nguyen Ngoc、Verma Ishwar C.、Bijarnia-Mahay Sunita、Lee Dong Hwan、Niu Dau-Ming、Hoffmann Georg F.、Shigematsu Yosuke、Fukao Toshiyuki、Fukuda Seiji、Taketani Takeshi、Yamaguchi Seiji
  • Journal Title: Molecular Genetics and Metabolism Reports Volume: 16 Pages: 5-10
  • DOI: 10.1016/j.ymgmr.2018.05.003
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Management and diagnosis of mitochondrial fatty acid oxidation disorders: focus on very-long-chain acyl-CoA dehydrogenase deficiency (2018)
  • Author(s): Yamada Kenji、Taketani Takeshi
  • Journal Title: Journal of Human Genetics Volume: 64 Issue: 2 Pages: 73-85
  • DOI: 10.1038/s10038-018-0527-7
  • Peer Reviewed
• [Journal Article] 新生児スクリーニングで異常を認めず、横紋筋融解症を機にカルニチンパルミトイルトランスフェラーゼ2（CPT）2欠損症と診断された幼児例 (2018)
  • Author(s): 李知子、山本和宏、起塚庸、山田健治、小林弘典、湯浅光織、重松陽介、原圭一、但馬剛、竹島泰弘．
  • Journal Title: 日本マススクリーニング学会誌 Volume: 28 Pages: 64-70
  • Peer Reviewed
• [Journal Article] Open-label clinical trial of bezafibrate treatment in patients with fatty acid oxidation disorders in Japan (2018)
  • Author(s): Yamada K, Shiraishi H, Oki E, Ishige M, Fukao T, Hamada Y, Sakai N, Ochi F, Watanabe A, Kawakami S, Kuzume K, Watanabe K, Sameshima K, Nakamagoe K, Tamaoka A, Asahina N, Yokoshiki S, Miyakoshi T, Ono K, Oba K, Isoe T, Hayashi H, Yamaguchi S, Sato N
  • Journal Title: Molecular Genetics and Metabolism Reports Volume: 15 Pages: 55-63
  • DOI: 10.1016/j.ymgmr.2018.02.003
  • NAID: 120006491518
  • Peer Reviewed / Open Access
• [Journal Article] A newborn case with carnitine palmitoyltransferase II deficiency initially judged as unaffected by acylcarnitine analysis soon after birth (2017)
  • Author(s): Yamada Kenji、Bo Ryosuke、Kobayashi Hironori、Hasegawa Yuki、Ago Mako、Fukuda Seiji、Yamaguchi Seiji、Taketani Takeshi
  • Journal Title: Molecular Genetics and Metabolism Reports Volume: 11 Pages: 59-61
  • DOI: 10.1016/j.ymgmr.2017.04.008
  • NAID: 120006373818
  • Peer Reviewed / Open Access
• [Journal Article] Clinical and molecular investigation of 14 Japanese patients with complete TFP deficiency: a comparison with Caucasian cases (2017)
  • Author(s): Bo Ryosuke、Yamada Kenji、Kobayashi Hironori、Jamiyan Purevsuren、Hasegawa Yuki、Taketani Takeshi、Fukuda Seiji、Hata Ikue、Niida Yo、Shigematsu Yosuke、Iijima Kazumoto、Yamaguchi Seiji
  • Journal Title: Journal of Human Genetics Volume: 62 Issue: 9 Pages: 809-814
  • DOI: 10.1038/jhg.2017.52
  • Peer Reviewed / Open Access
• [Journal Article] Newborn screening for carnitine palmitoyltransferase II deficiency using (C16 + C18:1)/C2: Evaluation of additional indices for adequate sensitivity and lower false-positivity (2017)
  • Author(s): Tajima G, Hara K, Tsumura M, Kagawa R, Okada S, Sakura N, Maruyama S, Noguchi A, Awaya T, Ishige N, Musha I, Ajihara S, Ohtake A, Naito E, Hamada Y, Kono T, Asada T, Sasaio H, Fukaoo T, Fujikip R, Ohara O, Bo R, Yamada K, Kobayashi H, Hasegawa Y, Yamaguchi S, Takayanagis M, Hata I, Shigematsu Y, Kobayashi M
  • Journal Title: Molecular Genetics and Metabolism Volume: 122 Issue: 3 Pages: 67-75
  • DOI: 10.1016/j.ymgme.2017.07.011
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy of bezafibrate on fibroblasts of glutaric acidemia type II patients evaluated using an in vitro probe acylcarnitine assay. (2017)
  • Author(s): Yamada K, Kobayashi H, Bo R, Purevsuren J, Mushimoto Y, Takahashi T, Hasegawa Y, Taketani T, Fukuda S, Yamaguchi
  • Journal Title: Brain and Development Volume: 39 Issue: 1 Pages: 48-27
  • DOI: 10.1016/j.braindev.2016.08.004
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] First Japanese Case of Carnitine Palmitoyltransferase II Deficiency with the Homozygous Point Mutation S113L (2016)
  • Author(s): Shima A, Yasuno T, Yamada K, Yamaguchi M, Kohno R, Yamaguchi S, Kido H, Fukuda H.
  • Journal Title: Internal Medicine Volume: 55 Issue: 18 Pages: 2659-2661
  • DOI: 10.2169/internalmedicine.55.6288
  • NAID: 130005414841
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access
• [Journal Article] A case of very-long-chain acyl-coenzyme A dehydrogenase deficiency with novel compound heterozygous mutations (2016)
  • Author(s): 7) Yamamoto F, Nakamagoe K, Yamada K, Ishii A, Furuta J, Yamaguchi S, Tamai A
  • Journal Title: Journal of the Neurological Sciences Volume: 368 Pages: 165-167
  • DOI: 10.1016/j.jns.2016.07.007
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Clinical Features of Carnitine Deficiency Secondary to Pivalate-Conjugated Antibiotic Therapy (2016)
  • Author(s): Kobayashi H, Fukuda S, Yamada K, Hasegawa Y, Takahashi T, Purevsuren J, Yamaguchi S
  • Journal Title: J Pediatr. Volume: April Pages: 183-187
  • DOI: 10.1016/j.jpeds.2016.02.080
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] CPT-2欠損症の同胞例、出生直後のアシルカルニチン分析で診断出来なかった1例 (2016)
  • Author(s): 山田健治、坊亮輔、小林弘典、長谷川有紀、山口清次
  • Journal Title: 特殊ミルク情報 Volume: 52 Pages: 52-55
• [Presentation] VLCAD欠損症の診断指標の検討：ろ紙血および血清のC14:1、C14:1/C2比、C14:1/C12:1比、C14:1/C16比の比較 (2019)
  • Author(s): 山田健治、大澤好充、小林弘典、長谷川有紀、山口清次、竹谷健
  • Organizer: 第61回日本先天代謝異常学会総会
• [Presentation] 追跡可能な成人ホモシスチン尿症患者の主治医を対象にした長期予後のアンケート調査 (2019)
  • Author(s): 山田健治、山口清次、竹谷健、横山和紀、青木菊麿
  • Organizer: 第46回日本マススクリーニング学会
• [Presentation] 出生直後のアシルカルニチン分析で診断できなかったCPT2欠損症の一例 (2018)
  • Author(s): 山田健治,小林弘典, 長谷川有紀, 山口清次, 竹谷健
  • Organizer: 第45回日本マススクリーニング学会
• [Presentation] 精度管理が可能な新規血清アシルカルニチン分析法の開発と旧来法との比較検討 (2018)
  • Author(s): 小林弘典、山田健治、長谷川有紀、梶谷晴香、山田健治、城下友義、大山直子、井手野晃、竹谷健
  • Organizer: 第45回日本マススクリーニング学会
• [Presentation] 新生児タンデムマススクリーニングで異常指摘されず、横紋筋融解症を機にCPT2欠損症と診断された幼児例 (2018)
  • Author(s): 李知子、山本和宏、山田健治、小林弘典、湯浅光織、重松陽介、但馬剛、竹島泰弘
  • Organizer: 第45回日本マススクリーニング学会
• [Presentation] 新生児マススクリーニングを契機に発見されたFLAD1変異によるグルタル酸血症2型の一例 (2018)
  • Author(s): 山田健治、伊藤道徳、小林弘典、長谷川有紀、山口清次、竹谷健
  • Organizer: 第60回日本先天代謝異常学会総会
• [Presentation] 脂肪酸代謝異常症の診断と治療（VLCAD欠損症とGA2を中心に） (2018)
  • Author(s): 山田健治
  • Organizer: 九州先天代謝異常症診療ネットワーク会議2018
  • Invited
• [Presentation] CPT-2欠損症による突然死の予防 ～拡大スクリーニング後にCPT-2欠損症と診断された1例を通して～ (2017)
  • Author(s): 山田健治、坊亮輔、小林弘典、長谷川有紀 、山口清次
  • Organizer: 日本SIDS・乳幼児突然死予防学会学術集会
  • Place of Presentation: 津アストホール（三重、津）
  • Year and Date: 2017-03-17
• [Presentation] 成人フェニルケトン尿症患者の生活状況調査：新生児マススクリーニングの効果の検討 (2017)
  • Author(s): 山田健治、青木菊麿、横山和紀、新宅治夫、上家和子、山口清次
  • Organizer: 第44回日本マススクリーニング学会
• [Presentation] 脂肪酸代謝異常症に対するベザフィブラートのオープンラベル臨床治験結果 (2017)
  • Author(s): 山田健治, 白石秀明, 朝比奈直子, 横式沙紀, 宮腰崇, 大野浩太, 磯江敏幸, 林宏至, 山口清次, 佐藤典宏
  • Organizer: 第59回日本先天代謝異常学会総会
• [Presentation] 新生児マススクリーニングで発見された日本人グルタル酸血症2型5例のまとめ (2017)
  • Author(s): 山田健治, 小林弘典, 長谷川有紀, 高橋明雄, 新宅治夫, 笹井英雄, 深尾敏幸, 山口清次, 竹谷健
  • Organizer: 第59回日本先天代謝異常学会総会
• [Presentation] 突然死を予防するために頻回の入院管理を行っているCPT-2欠損症の3歳女児例 (2017)
  • Author(s): 山田健治, 坊亮輔, 小林弘典, 長谷川有紀, 山口清次, 竹谷健
  • Organizer: 第69回中国四国小児科学会
• [Presentation] Neurological outcome of adult PKU patients detected by NBS in JAPAN (2017)
  • Author(s): Yamada K, Aoki K, Yokoyama K, Kobayashi H, Hasegawa Y, Tajima G, Shintaku H, Taketani T, Yamaguchi S
  • Organizer: 10th ISNS-ASIA PACIFIC REGIONAL MEETING 2017
  • Int'l Joint Research
• [Presentation] RIトレーサー法によるβ酸化能評価とin vitro probeアッセイの比較：ベザフィブラートの反応性について (2016)
  • Author(s): 山田健治，坊 亮輔，小林弘典，長谷川有紀，山口清次，竹谷健
  • Organizer: 日本先天代謝異常学会
  • Place of Presentation: 京王プラザホテル（東京、新宿）
  • Year and Date: 2016-10-27
• [Presentation] The effect of riboflavin is limited in Japanese patients with glutaric acidemia type II (2016)
  • Author(s): Kenji Yamada, Hironori Kobayashi, Yuki Hasegawa, Seiji Yamaguchi
  • Organizer: Society for the Study of Inborn Errors of Metabolism
  • Place of Presentation: Italia, Roma
  • Year and Date: 2016-09-06
  • Int'l Joint Research
• [Book] よくわかる新生児マススクリーニングガイドブック (2019)
  • Author(s): 山口 清次
  • Total Pages: 220
  • Publisher: 診断と治療社
  • ISBN: 9784787823892