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リソゾーム病の神経病変を標的とした新規遺伝子治療の開発

针对溶酶体疾病神经病变的新型基因疗法的开发

基本信息

批准号：
18790235
负责人：
三宅紀子
金额：
$ 2.11万
依托单位：
Nippon Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

リソゾーム酵素欠損症(以下リソゾーム病)は、精製した欠損酵素を定期的に静脈注射する酵素補充療法の有効性が確認されている。しかし、アリルスルファターゼA(ASA)の欠損症である異染性白質ジストロフィー(MLD)のような神経変性を伴う疾患に対しては血液脳関門(BBB)の存在が大きな障害となり、有効な治療戦略が立てられていない。本研究ではMLDの神経症状を非侵襲的に治療する新しいアデノ随伴ウイルス(AAV)ベクターの開発を目的とし、細胞膜通過活性をもつているHIVのTat配列とASAのキメラ蛋白遺伝子をAAVベクターに組み込み、遺伝子導入効率、発現効率の高い8型組替えAAVベクターを作製した。このベクターを6週令のMLDモデルマウスに静脈注射し、血清中のASA蛋白の推移を検討したところ、静脈注射後2週前後で高濃度のASAが検出されるもその後徐々に低下し、1ケ月後には検出不可能となった。これらのマウスにはASA中和抗体の上昇が認められ、また、同じベクターを免疫不全マウスに静脈注射したところ、長期にわたり高濃度のASA蛋白が認められたことにより、免疫反応の関与が示唆された。これを克服すべく、同じベクターを用いて新生児のMLDモデルマウスに静脈注射したところ、長期にわたり血清中のASA蛋白が認められ免疫寛容が認められた。新生児においては免疫反応、BBBともに未熟であり、AAVベクターの新生時時期における静脈注射はMLDのような神経症状を伴うリソゾーム病に有用な治療法になると考えられた。

There is a sexual confirmation that the enzyme deficiency syndrome (the following disease) and the regular "intravenous injection" of the enzyme deficiency syndrome (the following disease). A (ASA) deficiency syndrome (MLD), which is associated with the presence of a major disorder (BBB), is associated with the presence of a major disorder and treatment. In this study, patients with non-invasive symptoms of MLD were treated with a new treatment protocol (AAV). The purpose of this study was to detect the activity of ASA protein in the cell membrane through the active cell membrane, and to match the expression of ASA protein, protein, AAV, protein, gene, and so on. In this study, the clinical symptoms of non-invasive symptoms of MLD were not invasive. in this study, the treatment of non-invasive symptoms was not invasive. The purpose of this study was to provide information on the treatment of patients with non-invasive symptoms in this study. The purpose of this study was to treat the patients with non-invasive symptoms. The purpose of this study was to provide information on the treatment of patients with non-invasive symptoms. The purpose of this study was to use the active cell membrane to match the expression of AAV protein in the cell membrane. The MLD protein was injected intravenously, the serum ASA protein was injected intravenously, the ASA was elevated 2 months before and after the injection, and it was not possible to get low after 1 month. The antibody was neutralized by ASA, and the immune insufficiency was detected by intravenous injection. The ASA protein was confirmed to be high, and the immune response was detected. In order to overcome the problem, we should use the same method to treat the new-born MLD virus by intravenous injection of ASA protein in the serum for a long period of time. The immune response of newborn mice, the immune response of BBBs, the immature ones of BBBs, and the intravenous injection of MLD during the newborn period were used to treat the symptoms of the disease with the symptoms of the disease.