Immune responses to dystropin: implications for gene therapy of Duchenne muscular dystrophy.
Immune responses to dystropin: implications for gene therapy of Duchenne muscular dystrophy.
复制标题
对肌营养不良蛋白的免疫反应：对杜氏肌营养不良症基因治疗的影响。
作者：
A. Ferrer;K. Wells;D. Wells
通过基因转移将肌营养不良蛋白引入杜氏肌营养不良症 (DMD) 患者的营养不良肌肉中，有可能触发免疫反应，因为许多患者不会暴露于肌营养不良蛋白的部分（或全部）表位。这反过来可能导致转染的肌肉纤维的细胞毒性破坏。我们使用质粒 DNA 作为基因转移系统，在肌营养不良蛋白缺陷的 mdx 小鼠中评估了此类问题。这避免了与施用病毒蛋白相关的并发症。编码小鼠全长或截短的微型肌营养不良蛋白的 cDNA 的基因转移不会引起体液或细胞毒性免疫反应。 Mdx 小鼠可能具有耐受性，因为其骨骼肌中存在罕见的“回复型”肌营养不良蛋白阳性纤维。相反，人全长或小型肌营养不良蛋白的基因转移引起体液和细胞毒性反应，导致转染纤维的破坏。这些实验证明了 DMD 患者基因治疗后存在有害影响的潜在风险，并使我们建议参加基因治疗试验的患者理想情况下应该有小的、最好是点突变和“回复”肌营养不良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 all) 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.