Sharma D, Al-Khalidi R, Edgar S, An Q, Wang Y, Young C, Nowis D, Gorecki D C
Institute of Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK.
Department of Immunology, Center for Biostructure Research, Medical University of Warsaw, Warsaw, Poland.
Gene Ther. 2017 Feb;24(2):113-119. doi: 10.1038/gt.2016.82. Epub 2016 Dec 22.
A significant problem affecting gene therapy approaches aiming at achieving long-term transgene expression is the immune response against the protein product of the therapeutic gene, which can reduce or eliminate the therapeutic effect. The problem is further exacerbated when therapy involves targeting an immunogenic tissue and/or one with a pre-existing inflammatory phenotype, such as dystrophic muscles. In this proof-of-principle study, we co-expressed a model antigen, bacterial β-galactosidase, with an immunosuppressive factor, indoleamine 2,3-dioxygenase 1 (IDO1), in muscles of the mdx mouse model of Duchenne muscular dystrophy. This treatment prevented loss of expression of the transgene concomitant with significantly elevated expression of T-regulatory (Treg) markers in the IDO1-expressing muscles. Moreover, co-expression of IDO1 resulted in reduced serum levels of anti-β-gal antibodies. These data indicate that co-expression of genes encoding immunomodulatory enzymes controlling kynurenine pathways provide a viable strategy for preventing loss of transgenes targeted into dystrophic muscles with pre-existing inflammation.
影响旨在实现长期转基因表达的基因治疗方法的一个重大问题是针对治疗基因蛋白质产物的免疫反应，这可能会降低或消除治疗效果。当治疗涉及靶向免疫原性组织和/或具有预先存在的炎症表型的组织（如营养不良的肌肉）时，这个问题会进一步恶化。在这项原理验证研究中，我们在杜兴氏肌肉营养不良症的mdx小鼠模型的肌肉中共同表达了一种模型抗原——细菌β-半乳糖苷酶和一种免疫抑制因子——吲哚胺2,3-双加氧酶1（IDO1）。这种治疗方法防止了转基因表达的丧失，同时在表达IDO1的肌肉中，T调节（Treg）标志物的表达显著升高。此外，IDO1的共同表达导致血清中抗β-半乳糖抗体水平降低。这些数据表明，共同表达编码控制犬尿氨酸途径的免疫调节酶的基因，为防止靶向进入已有炎症的营养不良肌肉中的转基因丧失提供了一种可行的策略。
