摘要
转基因表达的免疫应答继续妨碍基因治疗的发展。已翻译的外源蛋白胞内定位一般难以接近免疫系统,但是他们可以通过MHC I 类和II类分子途径出现在免疫系统中。随着远交小鼠质粒DNA的肌内投递,当外源蛋白荧光素酶表达时,其表达时间下降到4周。通过表达质粒和荧光素酶转基因的修饰,我们检测了远离抗原递呈细胞 (APCs)靶向抑制表达和骨骼肌及甘氨酰胺核苷酸(GAr) 融合的靶向表达的作用,他们会阻止MHC I 类分子出现在荧光霉素表达的持续时间。来自APCs的miR142-3p 3’端非翻译区荧光素酶靶序列的靶向抑制表达可以减少内源基因和表达时间未延长的GAr短序列修饰的荧光素酶的体液免疫应答。当骨骼肌的特异启动子与miR靶序列结合时,体液免疫应答受到抑制并且萤光素酶以更持久更高水平的状态表达。有趣的是,萤光素酶与较长的Gar序列结合会促进降低萤光素酶的表达,增加萤光素酶体液免疫应答。这些研究表明表达因素和转基因修饰可以改变转基因表达的持续时间,但是在骨骼肌的外源转基因表达前需要克服,其它因素处于免疫静默状态。
关键词: 基因治疗,荧光素酶,microRNA,质粒DNA,骨骼肌,组织特异启动子,转基因致免疫性
Current Gene Therapy
Title:Effects of APC De-Targeting and GAr Modification on the Duration of Luciferase Expression from Plasmid DNA Delivered to Skeletal Muscle
Volume: 15 Issue: 1
Author(s): Maria C. Subang, Rewas Fatah, Ying Wu, Drew Hannaman, Jason Rice, Claire F. Evans, Yuti Chernajovsky and David Gould
Affiliation:
关键词: 基因治疗,荧光素酶,microRNA,质粒DNA,骨骼肌,组织特异启动子,转基因致免疫性
摘要: Immune responses to expressed foreign transgenes continue to hamper progress of gene therapy development. Translated foreign proteins with intracellular location are generally less accessible to the immune system, nevertheless they can be presented to the immune system through both MHC Class I and Class II pathways. When the foreign protein luciferase was expressed following intramuscular delivery of plasmid DNA in outbred mice, expression rapidly declined over 4 weeks. Through modifications to the expression plasmid and the luciferase transgene we examined the effect of detargeting expression away from antigen-presenting cells (APCs), targeting expression to skeletal muscle and fusion with glycine-alanine repeats (GAr) that block MHC-Class I presentation on the duration of luciferase expression. De-targeting expression from APCs with miR142-3p target sequences incorporated into the luciferase 3’UTR reduced the humoral immune response to both native and luciferase modified with a short GAr sequence but did not prolong the duration of expression. When a skeletal muscle specific promoter was combined with the miR target sequences the humoral immune response was dampened and luciferase expression persisted at higher levels for longer. Interestingly, fusion of luciferase with a longer GAr sequence promoted the decline in luciferase expression and increased the humoral immune response to luciferase. These studies demonstrate that expression elements and transgene modifications can alter the duration of transgene expression but other factors will need to overcome before foreign transgenes expressed in skeletal muscle are immunologically silent.
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Maria C. Subang, Rewas Fatah, Ying Wu, Drew Hannaman, Jason Rice, Claire F. Evans, Yuti Chernajovsky and David Gould , Effects of APC De-Targeting and GAr Modification on the Duration of Luciferase Expression from Plasmid DNA Delivered to Skeletal Muscle, Current Gene Therapy 2015; 15 (1) . https://dx.doi.org/10.2174/1566523214666141114204943
DOI https://dx.doi.org/10.2174/1566523214666141114204943 |
Print ISSN 1566-5232 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5631 |
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