Alton E W, Stern M, Farley R, Jaffe A, Chadwick S L, Phillips J, Davies J, Smith S N, Browning J, Davies M G, Hodson M E, Durham S R, Li D, Jeffery P K, Scallan M, Balfour R, Eastman S J, Cheng S H, Smith A E, Meeker D, Geddes D M
Department of Gene Therapy, Imperial College at National Heart and Lung Institute, London, UK.
Lancet. 1999 Mar 20;353(9157):947-54. doi: 10.1016/s0140-6736(98)06532-5.
We and others have previously reported significant changes in chloride transport after cationic-lipid-mediated transfer of the cystic fibrosis transmembrane conductance regulator (CFTR) gene to the nasal epithelium of patients with cystic fibrosis. We studied the safety and efficacy of this gene transfer to the lungs and nose of patients with cystic fibrosis in a double-blind placebo-controlled trial.
Eight patients with cystic fibrosis were randomly assigned DNA-lipid complex (active) by nebulisation into the lungs followed 1 week later by administration to the nose. Eight control patients followed the same protocol but with the lipid alone (placebo). Safety was assessed clinically, by radiography, by pulmonary function, by induced sputum, and by histological analysis. Efficacy was assessed by analysis of vector-specific CFTR DNA and mRNA, in-vivo potential difference, epifluorescence assay of chloride efflux, and bacterial adherence.
Seven of the eight patients receiving the active complex reported mild influenza-like symptoms that resolved within 36 h. Six of eight patients in both the active and placebo groups reported mild airway symptoms over a period of 12 h following pulmonary administration. No specific treatment was required for either event. Pulmonary administration resulted in a significant (p<0.05) degree of correction of the chloride abnormality in the patients receiving active treatment but not in those on placebo when assessed by in-vivo potential difference and chloride efflux. Bacterial adherence was also reduced. We detected no alterations in the sodium transport abnormality. A similar pattern occurred following nasal administration.
Cationic-lipid-mediated CFTR gene transfer can significantly influence the underlying chloride defect in the lungs of patients with cystic fibrosis.
我们和其他研究人员之前报道过，在通过阳离子脂质介导将囊性纤维化跨膜传导调节因子（CFTR）基因转移至囊性纤维化患者的鼻上皮细胞后，氯化物转运发生了显著变化。我们在一项双盲安慰剂对照试验中研究了这种基因转移对囊性纤维化患者肺部和鼻腔的安全性及有效性。
8名囊性纤维化患者被随机分配，通过雾化吸入将DNA -脂质复合物（活性药物）导入肺部，1周后再施用于鼻腔。8名对照患者遵循相同方案，但仅使用脂质（安慰剂）。通过临床评估、影像学检查、肺功能检查、诱导痰检查及组织学分析来评估安全性。通过分析载体特异性CFTR DNA和mRNA、体内电位差、氯化物外流的落射荧光测定以及细菌黏附情况来评估有效性。
8名接受活性复合物治疗的患者中有7名报告出现轻度流感样症状，这些症状在36小时内缓解。活性组和安慰剂组的8名患者中有6名在肺部给药后的12小时内报告出现轻度气道症状。这两种情况均无需特殊治疗。通过体内电位差和氯化物外流评估发现，接受活性治疗的患者肺部氯化物异常得到显著（p<0.05）程度的纠正，而接受安慰剂治疗者则未出现这种情况。细菌黏附也有所减少。我们未检测到钠转运异常有改变。鼻腔给药后出现了类似的情况。
阳离子脂质介导的CFTR基因转移可显著影响囊性纤维化患者肺部潜在的氯化物缺陷。
