Structure-based modification of lysosomal enzymes: development of new enzyme replacement therapy for lysosomal diseases

• Project/Area Number: 18390303
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Meiji Pharmaceutical University (2007-2008); Tokyo Metropolitan Organization for Medical Research (2006)
• Principal Investigator: SAKURABA Hitoshi Meiji Pharmaceutical University, 薬学部, 教授 (60114493)
• Research Collaborator: TOGAWA Tadayasu 明治薬科大学, 薬学部, 准教授 (80260983) ; SUZUKI Toshihiro 明治薬科大学, 薬学部, 講師 (80322527) ; SUGAWARA Kanako 明治薬科大学, 薬学部, 助教 (00551087) ; ITOH Kohji 徳島大学, 大学院ヘルスバイオサイエンス研究部, 教授 (00184656)
• Project Period (FY): 2006 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥11,690,000 (Direct Cost: ¥10,100,000、Indirect Cost: ¥1,590,000); Fiscal Year 2008: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2007: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2006: ¥4,800,000 (Direct Cost: ¥4,800,000)
• Keywords: リソソーム病 / ファブリー病 / α-ガラクトシダーゼ / GM2ガングリオシドーシス / テイ-サックス病 / ザンドホッフ病 / β-ヘキソサミニダーゼA / β-ヘキソサミニダーゼB / β-ヘキソミニダーゼA / 構造生物学 / 酵素補充療法

Research Abstract

リソソーム病に対して酵素補充療法が導入されたが、現在使用されている酵素薬には克服すべき多くの問題がある。そこで、リソソーム病の中でも重要なファブリー病とGM2ガングリオシドーシスに対して、夫々の疾患責任酵素に構造が似た酵素を、分子設計により改変し、基質特異性を変換した新規酵素を作製した。これらは、野生型酵素に比べて安定で、細胞内取り込みに優れ、アレルギー反応を起こし難いと考えられ、リソソーム病に対する新規酵素治療薬として期待出来る。

Research Products

• [Journal Article] Structural modeling of mutant α-glucosidases resulting in a processing/transport defect in Pompe disease. (2009)
  • Author(s): Sugawara K., Saito S., Sekijima M., Ohno K., Tajima Y., Kroos M.A., Reuser A.J.J., Sakuraba H.
  • Journal Title: J. Hum. Genet., Doi:10.1038/jhg. Pages: 32-32
  • NAID: 10030730594
• [Journal Article] Molecular interaction of imino sugars with human α-galactosidase: insight into the mechanism of complex formation and pharmacological chaperone action in Fabry disease. (2009)
  • Author(s): Sugawara K., Tajima Y., Kawashima I., Tsukimura T., Saito S., Ohno K., Iwamoto K., Kobayashi T., Itoh K., Sakuraba H.
  • Journal Title: Mol. Genet. Metab. 96 Pages: 233-238
• [Journal Article] Structural characterization of mutant α-galactosidases causing Fabry disease. (2009)
  • Author(s): Sugawara K., Ohno K., Saito S., Sakuraba H.
  • Journal Title: J. Hum. Genet. 53 Pages: 812-824
  • NAID: 10021929382
• [Journal Article] Molecular interaction of imino sugars with human a-galactosidase : insight into the mechanism of complex formation and pharmacological chaperone action in Fabry disease. (2009)
  • Author(s): Sugawara K., et al.
  • Journal Title: Mol. Genet. Meta. 96 Pages: 233-238
  • Peer Reviewed
• [Journal Article] Structural consequences of amino acid substitutions causing Tay-Sachs disease. (2008)
  • Author(s): Ohno K., Saito S., Sugawara K., Sakuraba H.
  • Journal Title: Mol. Genet. Metab. 94 Pages: 462-468
• [Journal Article] Structural characterization of mutant a-galactosidases causing Fabry disease. (2008)
  • Author(s): Sugawara K., et al.
  • Journal Title: J. Hum. Genet. 53 Pages: 812-824
  • Peer Reviewed
• [Journal Article] Structural cosequences of amino acid substitutions causing Tay-Sachs disease. (2008)
  • Author(s): Ohno K., et al.
  • Journal Title: Mol. Genet. Metab. 94 Pages: 462-468
  • Peer Reviewed
• [Journal Article] Structural and clinical implications of amino acid substitutions in N-acetylgalctsamine-4-sulfatase:Insight into mucopolysaccharidosis type VI (2008)
  • Author(s): Satito S, et. al.
  • Journal Title: Mol.Genet.Metab 93 Pages: 419-425
  • Peer Reviewed
• [Journal Article] Establishment of immortalized Schwann cells from Fabry mice and their low uptake of recombinant α-galactosidase. (2007)
  • Author(s): Kawashima I., Watabe K., Tajima Y., Fukushima T., Kanzaki T., Kanekura T., Sugawara K., Ohyanagi N., Suzuki T., Togawa T., Sakuraba H.
  • Journal Title: J. Hum. Genet. 52 Pages: 1018-1025
  • NAID: 10020022348
• [Journal Article] Structural and biochemical studies on Pompe disease and a "pesudodificiency of acid α-glucosidase" (2007)
  • Author(s): Tajima Y, et. al.
  • Journal Title: J.Hum.Genet 52 Pages: 898-906
  • Peer Reviewed
• [Journal Article] Establishment of immortalized Schwann cells from Fabry mice and their low uptake of recombinant α-galactosidase (2007)
  • Author(s): Kawashima I, et. al.
  • Journal Title: J.Hum.Genet 52 Pages: 1018-1025
  • Peer Reviewed
• [Journal Article] Corrective effect on Fabry mice of yeast recombinant human α-galactosidase with N-linked sugar chains suitable for lysosomal delivery. (2006)
  • Author(s): Sakuraba H., Chiba Y., Kotani M., Kawashima I., Ohsawa M., Tajima Y., Takaoka Y., Jigami Y., Takahashi H., Hirai Y., Shimada T., Hashimoto Y., Ishii K., Kobayashi T., Watabe K., Fukushige T., Kanzaki T.
  • Journal Title: J. Hum. Genet. 51 Pages: 341-352
  • NAID: 10017479857
• [Journal Article] Comparison of the effects of agalsidase alfa and agalsidase beta on cultured human Fabry fibroblasts and Fabry mice. (2006)
  • Author(s): Sakuraba H., Murata-Ohsawa M., Kawashima I., Tajima Y., Kotani M., Ohshima T., Chiba Y., Takashiba M., Jigami Y., Fukushige T., Kanzaki T., Itoh K.
  • Journal Title: J. Hum. Genet. 51 Pages: 180-188
  • NAID: 10018115555
• [Journal Article] Comparison of the effects of agalsidase alfa and agalsidase beta on cultured human Fabry fibroblasts and Fabry mice. (2006)
  • Author(s): Sakuraba, H., et al.
  • Journal Title: J.Hum.Genet. 51 Pages: 180-188
  • NAID: 10018115555
• [Journal Article] Corrective effect on Fabry mice of yeast recombinant human α-galactosidase with N-linked sugar chains suitable for lysosomal delivery. (2006)
  • Author(s): Sakuraba, H., et al.
  • Journal Title: J.Hum.Genet. 51 Pages: 341-352
  • NAID: 10017479857
• [Journal Article] Phospholipid storage in the myocardium of a unique Japanese case of idiopathic cardiomyopathy. (2006)
  • Author(s): Kawashima, T., et al.
  • Journal Title: Clin.Chim,Acta 372 Pages: 154-157
• [Journal Article] Molecular pathogenesis and enzyme replacement therapies for lysosomal diseases. (2006)
  • Author(s): Sakuraba, H., et al.
  • Journal Title: Curr.Drug Targets-Central Nervous System and Neurological Disorders. 5 Pages: 401-413
• [Journal Article] α-galactosidase A. (2006)
  • Author(s): 桜庭 均
  • Journal Title: 腎と透析 61 Pages: 288-290
• [Journal Article] Inefficiency in GM2 ganglioside elimination by human lysosomal β-hexosaminidase β-subunit gene transfer to fibroblastic cell line derived from Sandhoff disease model mice. (2006)
  • Author(s): Itakura, T,. et al.
  • Journal Title: Biol.Pharm.Bull. 29 Pages: 1564-1569
• [Presentation] ファブリー病の分子病態と診断・治療 (2008)
  • Author(s): 桜庭 均
  • Organizer: 第51回日本腎臓病学会学術総会 ランチョンセミナー21
  • Place of Presentation: 福岡
  • Year and Date: 2008-06-01
• [Presentation] フアブリー病の分子病態と診断・治療 (2008)
  • Author(s): 柳庭 均
  • Organizer: 第51回日本腎臓病学会学術総会
  • Place of Presentation: 福岡
  • Year and Date: 2008-06-01
• [Presentation] リソソーム病の酵素補充療法製剤の特徴~ファブリー病治療薬を中心に ランチョンセミナー (2008)
  • Author(s): 桜庭 均
  • Organizer: 第35回日本小児臨床薬理学会年会
  • Place of Presentation: 東京
• [Presentation] リソソーム病の新規治療法開発:脳障害克服を目指して (2008)
  • Author(s): 桜庭 均
  • Organizer: The 7th Cell Biology Summer Meeting
  • Place of Presentation: 鴨川
• [Presentation] リソソーム病の分子病態の解明-その治療に向かって (2008)
  • Author(s): 桜庭 均
  • Organizer: 日本薬学会第128年会シンポジウムS19
  • Place of Presentation: 横浜
• [Presentation] ファブリー病の病態と遺伝子変異 (2007)
  • Author(s): 桜庭 均
  • Organizer: 第29回心筋生検研究会,招待講演
  • Place of Presentation: 名古屋
• [Presentation] 先天代謝異常症における治療概説 (2007)
  • Author(s): 桜庭 均
  • Organizer: 第49回日本先天代謝異常学会, シンポジウム
  • Place of Presentation: 山形
• [Presentation] 先天代謝異常症における治療概説 (2007)
  • Author(s): 桜庭 均
  • Organizer: 第49回日本先天代謝異常学会
  • Place of Presentation: 山形
• [Book] 酸性α-グルコシダーゼとポンペ病. ポンペ病(衛藤義勝/監修) (2009)
  • Author(s): 桜庭 均, 菅原佳奈子
  • Publisher: 診断と治療社(東京)
• [Book] 異染性白質ジストロフィー.小児科学,第3版(大関武彦,近藤直実/総編集) (2008)
  • Author(s): 桜庭 均
  • Publisher: 医学書院(東京)
• [Book] Fabry病. 小児科学,第3版(大関武彦,近藤直実/総編集) (2008)
  • Author(s): 桜庭 均
  • Publisher: 医学書院(東京)
• [Book] 小児科学,第3版(大関武彦, 近藤直実/総編集) (2008)
  • Author(s): 根庭 均
  • Total Pages: 3
  • Publisher: 医学書院
• [Book] Fabry病. 今日の小児治療指針,第14版(大関武彦,古川 漸, 横田俊一郎/編) (2006)
  • Author(s): 桜庭 均
  • Publisher: 医学書院(東京)
• [Book] Fabry病.今日の小児治療指針,第14版(大関武彦, 古川 漸, 横田俊一郎/編) (2006)
  • Author(s): 桜庭 均
  • Total Pages: 2
  • Publisher: 医学書院(東京)
• [Patent(Industrial Property Rights)] ヒトβ-ヘキソサミニダーゼBの基質特異性を変換した新規高機能酵素 (2009)
  • Inventor(s): 櫻庭 均,伊藤孝司,辻 大輔
  • Industrial Property Rights Holder: 学校法人明治薬科大学
  • Industrial Property Number: 2009-008039
  • Filing Date: 2009-01-16
• [Patent(Industrial Property Rights)] ヒトβ-ヘキソサミニダーゼBの基質特異性を変換した新規高機能酵素 (2009)
  • Inventor(s): 櫻庭 均, 伊藤孝司, 辻 大輔
  • Industrial Property Rights Holder: 明治薬科大学
  • Industrial Property Number: 2009-008039
  • Filing Date: 2009-01-16