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Longterm gene therapy of xeroderma pigmentosum group A mice using HVJ-liposomes.

使用 HVJ 脂质体对着色性干皮病 A 组小鼠进行长期基因治疗。

基本信息

批准号：
14370258
负责人：
NISHIGORI Chikako
金额：
$ 5.31万
依托单位：
Kobe University (2003)Kyoto University (2002)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

项目摘要

Xeroderma pigmentosum (XP) is an autosomalrecessibely inheritated disorder in which nucleotide excision repair is deficient, thus the patients with XP cause skin cancer of sun-exposed area in high frequency. Among XP complementation groups, XP complementation group A (XPA) reveals the severest clinical phenotype with neurological abnormalities and XPA is the most common type among Japanese XPA patients. The aim of this project is to challenge the gene therapy of XPA model mice in vivo with treating human XPA gene in the form of HVJ-liposomes, since one of our research goal is to establish the gene therapy for XPA patients. Two plasmids containing human XPA gene, pCAGGS-XPA or pcHA-XPA, which contains hemagultinin gene as a tag, was transfected and the repair ability was measured by unscheduled DNA syntshesis at post 24 or 48 hr UVC irradiation. Both recovered the repair efficiency in XPA mice cells. In in vivo study HVJ (Hemagluutinating Virus of Japan)-liposomes was used for introducing the plasmid containing human XPA gene into mice skin. HVJ-liposomes-XPA was injected intradermaly 24 hr before 4 kJ/m^2 of UVB irradiation or topically painted 48 hr before UVB irradiation. Unscheduled DNA synthesis of epidermal nuclei in mice injected XPA-HVJ liposmes was higher than that of control liposomes. Next we irradiated the mice with 500 J/m^2 of UVB 1-2 times per week for 3 months with or without treating HVJ-XPA-liposmes 24 or 48 hr prior to UVB irradiation. Both pcHA-XPA and pCAGGS-XPA encapsulated in HVJ-liposmes reduced the size, the number of the UV-induced tumors and elongate the survival duration. However, both treatment did not completely inhibit the tumor formation. The histology of the tumor was squamous cell carcinoma. In conclusion, the treatment of HVJ-XPA liposomes has effect on reducing the UV-induced tumors in XPA model mice.

色素性干皮病（XP）是一种常染色体隐性遗传性疾病，由于核苷酸切除修复缺陷，因此XP患者引起日晒部位皮肤癌的几率较高。在 XP 互补组中，XP 互补组 A (XPA) 表现出最严重的神经系统异常临床表型，XPA 是日本 XPA 患者中最常见的类型。本项目的目的是通过以HVJ-脂质体的形式处理人类XPA基因来挑战XPA模型小鼠的体内基因治疗，因为我们的研究目标之一是建立针对XPA患者的基因治疗。转染含有人XPA基因的两个质粒pCAGGS-XPA或pcHA-XPA（其含有血凝素基因作为标签），并通过在UVC照射24或48小时后的计划外DNA合成来测量修复能力。两者都恢复了 XPA 小鼠细胞的修复效率。在体内研究中，使用HVJ（日本血凝病毒）脂质体将含有人XPA基因的质粒导入小鼠皮肤中。 HVJ-脂质体-XPA 在 4 kJ/m^2 UVB 照射前 24 小时皮内注射，或在 UVB 照射前 48 小时局部涂抹。注射XPA-HVJ脂质体的小鼠表皮细胞核的非计划DNA合成高于对照脂质体。接下来，我们用 500 J/m^2 的 UVB 每周 1-2 次照射小鼠，持续 3 个月，在 UVB 照射前 24 或 48 小时处理或不处理 HVJ-XPA-脂质体。封装在 HVJ 脂质体中的 pcHA-XPA 和 pCAGGS-XPA 均减少了紫外线诱导的肿瘤的大小和数量，并延长了存活时间。然而，两种治疗都没有完全抑制肿瘤的形成。肿瘤的组织学为鳞状细胞癌。总之，HVJ-XPA脂质体治疗具有减少XPA模型小鼠紫外线诱导肿瘤的作用。