Development of efficient enzyme replacement therapy for lysosomal storage disease with immune modulation

Research Project

Project/Area Number	15K09600
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Research Field	Pediatrics
Research Institution	Jikei University School of Medicine
Principal Investigator	Ohashi Toya 東京慈恵会医科大学, 医学部, 教授 (60160595)
Co-Investigator(Kenkyū-buntansha)	嶋田洋太東京慈恵会医科大学, 医学部, 助教 (20560824) 樋口孝東京慈恵会医科大学, 医学部, 助教 (30595327) 小林博司東京慈恵会医科大学, 医学部, 准教授 (90266619) 横井健太郎東京慈恵会医科大学, 医学部, 講師 (20459655)
Project Period (FY)	2015-04-01 – 2018-03-31
Project Status	Completed (Fiscal Year 2017)
Budget Amount *help	¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000) Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000) Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000) Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords	遺伝・先天異常 / 先天代謝異常症 / 酵素補充療法 / 免疫寛容 / ライソゾーム病 / 抗体 / 先天代謝異常 / 遺伝・先天異常学 / 先天代謝異常学
Outline of Final Research Achievements	Lysosomal storage disease (LSD) are characterized by genetic deficiency of lysosomal enzyme, resulting in accumulation of its substrate in various organ. As a treatment, enzyme replacement therapy (ERT) is available. ERT is very efficient, but immune reaction against infused enzyme was occurred. This causes development of neutralizing antibody. ERT has another limitation, which is ineffectiveness to brain disease because of presence of BBB. To overcome these two problem, we tested various approach. The positive results were obtained following two experiment. (1)Anti-Blys antibody successfully reduce immune reaction of ERT on murine model of Fabry disease and increased efficacy of ERT. (2)Huge amount of enzyme administration reduced accumulated compound in brain from mucopolysaccharidosis type II mice without immune reaction against enzyme by anti-CD3 antibody administration.