Limberis Maria, Anson Donald S, Fuller Maria, Parsons David W
Department of Pulmonary Medicine, Women's and Children's Hospital, North Adelaide, South Australia, 5006, Australia.
Hum Gene Ther. 2002 Nov 1;13(16):1961-70. doi: 10.1089/10430340260355365.
The potential for gene therapy to be an effective treatment for cystic fibrosis (CF) airway disease has been limited by inefficient gene transfer vector particle delivery and lack of persistent gene expression. We have developed an airway conditioning process that, when combined with a human immunodeficiency virus (HIV)-derived lentivirus (LV) vector, resulted in persistent in vivo expression of transgenes in airway epithelium. Pretreatment of mouse nasal epithelium with the detergent lysophosphatidylcholine (LPC) prior to instillation of a single dose of an LV vector carrying the LacZ marker gene produced significant LacZ gene expression in nasal airway epithelium for at least 92 days. Transduction of the cystic fibrosis transmembrane conductance regulator (CFTR) gene using the same LV vector system resulted in partial recovery of electrophysiologic function in the nasal airway epithelium of CF mice (cftr(tm1Unc) knockout) for at least 110 days. This first demonstration of LV-mediated in vivo recovery of CFTR function in CF airway epithelium illustrates the potential of combining a preconditioning of the airway surface with a simple and brief LV vector exposure to produce therapeutic gene expression in airway.
基因治疗作为囊性纤维化（CF）气道疾病有效治疗方法的潜力一直受到基因传递载体颗粒递送效率低下以及缺乏持续基因表达的限制。我们开发了一种气道预处理方法，当与源自人类免疫缺陷病毒（HIV）的慢病毒（LV）载体相结合时，可在气道上皮细胞中实现转基因的持续体内表达。在滴注携带LacZ标记基因的单剂量LV载体之前，用去污剂溶血磷脂酰胆碱（LPC）对小鼠鼻上皮进行预处理，可在鼻气道上皮中产生显著的LacZ基因表达，持续至少92天。使用相同的LV载体系统转导囊性纤维化跨膜传导调节因子（CFTR）基因，可使CF小鼠（cftr(tm1Unc)基因敲除）鼻气道上皮的电生理功能部分恢复，持续至少110天。LV介导CF气道上皮细胞中CFTR功能体内恢复的首次证明，说明了将气道表面预处理与简单短暂的LV载体暴露相结合以在气道中产生治疗性基因表达的潜力。
