Basic research for the efficiency of enzyme therapy for glycogen storage disease type II (pompe disease)

酶疗法治疗 II 型糖原累积病（庞贝病）有效性的基础研究

• 批准号: 17591097
• 负责人: IKEZAWA Makoto
• 金额: $ 2.24万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591097/
• 关键词: Pompe disease; Enzyme therapy; Missense mutation; Antibody

Glycogen storage disease type II (Pompe disease) is caused by deficiency of acid alpha-glucosidase resulting in accumulations of glycogen in multiple tissues. Some reports of enzyme therapy using recombinant human acid alpha-glucosidase (rhGAA) showed clinical improvement of infantile Pompe disease in a few cases, and production of anti-rhGAA antibody might reduce the effectiveness of rhGAA therapy.A two years old Japanese girl with Pompe disease had attended a year of international clinical trial of rhGAA and came back to Japan. We succeeded her enzyme therapy with rhGAA (Genzyme Japan). Her cardiac dysfunction was improving and a report from UK suggests no anti-rhGAA antibody production. We followed her clinical course and investigate genetic background to develop more efficient enzyme for enzyme replacement therapy.1. rhGAA therapy for Pompe disease.We injected rhGAA every two weeks to a Japanese three years old girl with Pompe disease with agreement of her parents. She was often suffered from respiratory infections and her enzyme injection was sometimes postponed by reasons of her infections or her parents' inconvenience. After over a month of postpone of injection, she was affected with severe pneumonia and required mechanical ventilation support and intensive care. She had recovered with injection of rhGAA and antibiotics, however she required trachecstomy and home oxygen therapy. She now takes injection every two weeks strictly and her cardiac function is almost normal.2. Acid alpha-glucosidase gene mutation analysis.We extracted DNA and total RNA from patient's skin fibroblast and human acid alpha-glucosidase gene cDNA was amplified by conventional RT-PCR technique. Sequence analysis of cDNA showed a missence mutation (796C>T), which was already reported as pathological mutation.3. Investigation about immunogensity of rhGAA.After following injection of rhGAA, our patient produced anti-rhGAA antibody. Our analysis of her immune function was normal.

糖原累积病II型（庞贝氏病）是由酸性α-葡糖苷酶缺乏引起的，导致糖原在多种组织中积累。重组人酸性α-葡萄糖苷酶（rhGAA）治疗儿童庞贝氏症的临床疗效观察显示，rhGAA抗体的产生可能降低rhGAA治疗效果。我们成功地用rhGAA（Genzyme Japan）进行了酶治疗。她的心功能不全正在改善，英国的一份报告提示无抗rhGAA抗体产生。我们追踪她的临床过程并调查遗传背景，以开发更有效的酶替代疗法。我们每两周给一名患有庞贝氏症的日本三岁女孩注射一次rhGAA，并征得她父母的同意。她经常患有呼吸道感染，有时由于感染或父母不便而推迟注射酶。在推迟注射一个多月后，她患上了严重的肺炎，需要机械通气支持和重症监护。她通过注射rhGAA和抗生素恢复，但她需要气管造口术和家庭氧疗。她现在严格每两周注射一次，心脏功能基本正常。酸性α-葡萄糖苷酶基因突变分析：提取患者皮肤成纤维细胞DNA和总RNA，采用常规RT-PCR技术扩增人酸性α-葡萄糖苷酶基因cDNA。cDNA序列分析发现一个错义突变（796 C>T），该突变已被报道为病理性突变. rhGAA免疫原性的研究：本例患者注射rhGAA后产生了抗rhGAA抗体。我们对她免疫功能的分析是正常的。