Immune responses to dystrophin: implications for gene therapy of Duchenne muscular dystrophy
Immune responses to dystrophin: implications for gene therapy of Duchenne muscular dystrophy
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DOI：
10.1038/sj.gt.3301259
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发表时间：
2000-09-01
期刊：
影响因子：
5.1
通讯作者：
Wells, DJ
中科院分区：
文献类型：
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作者：
Ferrer, A;Wells, KE;Wells, DJ
通过基因转移将抗肌萎缩蛋白导入杜氏肌营养不良（DMD）患者的营养不良肌肉中，有可能引发免疫反应，因为许多患者未曾接触过抗肌萎缩蛋白的某些（或全部）表位。这反过来可能导致转染的肌纤维发生细胞毒性破坏。我们使用质粒DNA作为基因转移系统，在抗肌萎缩蛋白缺陷的mdx小鼠中评估了此类担忧。这避免了与病毒蛋白给药相关的并发症。编码小鼠全长或截短的微型抗肌萎缩蛋白的cDNA的基因转移既未引发体液免疫反应，也未引发细胞毒性免疫反应。mdx小鼠可能由于其骨骼肌中存在罕见的“回复突变”抗肌萎缩蛋白阳性纤维而具有耐受性。相比之下，人全长或微型抗肌萎缩蛋白的基因转移引发了体液和细胞毒性反应，导致转染的纤维遭到破坏。这些实验证明了DMD患者在基因治疗后存在潜在有害影响的风险，并使我们建议，参加基因治疗试验的患者理想情况下应具有较小的（最好是点）突变以及“回复突变”抗肌萎缩蛋白阳性肌纤维的证据。
Introduction of dystrophin by gene transfer into the dystrophic muscles of Duchenne muscular dystrophy (DMD) patients has the possibility of triggering an immune response as many patients will not have been exposed to some (or ail) of the epitopes of dystrophin. This could in turn lead to cytotoxic destruction of transfected muscle fibres. We assessed such concerns in the dystrophin-deficient mdx mouse using plasmid DNA as the gene transfer system. This avoids complications associated with the administration of viral proteins. Gene transfer of cDNAs encoding mouse full-length or a truncated minidystrophin did not evoke either a humoral or cytotoxic immune response. Mdx mice may be tolerant due to the presence of rare 'revertant' dystrophin-positive fibres in their skeletal muscles. In contrast, gene transfer of human full-length or minidystrophin provoked both humoral and cytotoxic responses leading to destruction of the transfected fibres. These experiments demonstrate the potential risk of deleterious effects following gene therapy in DMD patients and lead us to suggest that patients enrolled in gene therapy trials should ideally have small, preferably point, mutations and evidence of 'revertant' dystrophin-positive muscle fibres.