Recovery of airway cystic fibrosis transmembrane conductance regulator function in mice with cystic fibrosis after single-dose lentivirus-mediated gene transfer
Recovery of airway cystic fibrosis transmembrane conductance regulator function in mice with cystic fibrosis after single-dose lentivirus-mediated gene transfer
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DOI：
10.1089/10430340260355365
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发表时间：
2002-11-01
影响因子：
4.2
通讯作者：
Parsons, DW
中科院分区：
文献类型：
--
作者：
Limberis, M;Anson, DS;Parsons, DW
基因治疗有效治疗囊性纤维化 (CF) 气道疾病的潜力受到基因转移载体颗粒递送效率低下和缺乏持久基因表达的限制。我们开发了一种气道调节过程，当与人类免疫缺陷病毒（HIV）衍生的慢病毒（LV）载体结合时，可导致转基因在气道上皮中持续表达。在滴注单剂量携带 LacZ 标记基因的 LV 载体之前，用去污剂溶血磷脂酰胆碱 (LPC) 预处理小鼠鼻上皮，在鼻气道上皮中产生显着的 LacZ 基因表达至少 92 天。使用相同的 LV 载体系统转导囊性纤维化跨膜电导调节因子 (CFTR) 基因，导致 CF 小鼠（cftr(tm1Unc) 敲除）鼻气道上皮电生理功能部分恢复至少 110 天。这首次证明了左心室介导的CF气道上皮中CFTR功能的体内恢复，说明了将气道表面的预处理与简单而短暂的左心室载体暴露相结合以在气道中产生治疗性基因表达的潜力。
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 electro-physiologic 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.