CTLA4Ig delivered by high-capacity adenoviral vector induces stable expression of dystrophin in mdx mouse muscle
CTLA4Ig delivered by high-capacity adenoviral vector induces stable expression of dystrophin in mdx mouse muscle
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DOI：
10.1038/sj.gt.3302315
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发表时间：
2004-10-01
期刊：
影响因子：
5.1
通讯作者：
Clemens, PR
中科院分区：
文献类型：
--
作者：
Jiang, Z;Schiedner, G;Clemens, PR
腺病毒（Ad）载体介导的正常全长肌营养不良蛋白基因传递到骨骼肌，为治疗杜氏肌营养不良症（DMD）提供了一种有希望的策略，DMD是一种x连锁隐性肌营养不良蛋白缺乏的肌肉疾病。动物模型研究表明，通过Ad载体介导的基因转移成功治疗DMD可能会受到载体衣壳和转基因蛋白诱导的细胞和体液免疫反应的阻碍。为了解决由肌酸激酶启动子（AdmDys）和mCTLA4Ig （Ad-mCTLA4Ig）单独或共同驱动的高容量腺病毒（HC-Ad）载体（AdmCTLA4Ig/mDys）介导的小鼠肌营养不良蛋白介导的免疫问题，我们开发了高容量腺病毒（HC-Ad）载体。我们发现，在mdx小鼠胫骨前肌中，共注射AdmCTLA4Ig和AdmDys，或单独注射AdmCTLA4Ig/mDys， dystrophin蛋白的表达稳定，而在AdmDys和空载体共注射的对照组中，dystrophin蛋白的表达在给药后2至8周内下降了至少50%。此外，与对照组相比，我们观察到在接受mctla4ig表达载体的两个实验组中，Ad载体诱导的Th1和Th2细胞因子，Ad载体特异性细胞毒性T淋巴细胞活化和中和抗Ad抗体的减少。本研究表明，HC-Ad载体介导的基因转移提供了mCTLA4Ig和肌营养不良蛋白在骨骼肌中的共表达，可以在免疫正常的成年mdx小鼠肌肉中稳定表达肌营养不良蛋白，并为克服Ad载体介导的肌营养不良蛋白基因传递诱导的适应性免疫提供了一种潜在的强大策略，从而达到治疗DMD的最终目的。
Adenoviral (Ad) vector-mediated gene delivery of normal, full-length dystrophin to skeletal muscle provides a promising strategy for the treatment of Duchenne muscular dystrophy (DMD), an X-linked recessive, dystrophin-deficient muscle disease. Studies in animal models suggest that successful DMD gene therapy by Ad vector-mediated gene transfer would be precluded by cellular and humoral immune responses induced by vector capsid and transgene proteins. To address the immunity induced by Ad vector-mediated dystrophin gene delivery to dystrophic muscle, we developed high-capacity adenoviral (HC-Ad) vectors expressing mouse dystrophin driven by the muscle creatine kinase promoter (AdmDys) and mCTLA4Ig (Ad-mCTLA4Ig) individually, or together from one vector ( AdmCTLA4Ig/mDys). We found stable expression of dystrophin protein in the tibialis anterior muscles of mdx mice, coinjected with AdmCTLA4Ig and AdmDys, or injected alone with AdmCTLA4Ig/mDys, whereas the expression of dystrophin protein in the control group coinjected with AdmDys and an empty vector decreased by at least 50% between 2 and 8 weeks after administration. Additionally, we observed reductions in Ad vector-induced Th1 and Th2 cytokines, Ad vector-specific cytotoxic T lymphocyte activation and neutralizing anti-Ad antibodies in both experimental groups that received a mCTLA4Ig-expressing vector as compared to the control group. This study demonstrates that the coexpression of mCTLA4Ig and dystrophin in skeletal muscle provided by HC-Ad vector-mediated gene transfer can provide stable expression of dystrophin in immunocompetent, adult mdx mouse muscle and applies a potentially powerful strategy to overcome adaptive immunity induced by Ad vector-mediated dystrophin gene delivery toward the ultimate goal of treatment for DMD.