Repeated aerosolized AAV-CFTR for treatment of cystic fibrosis: A Randomized placebo-controlled phase 2B trial
Repeated aerosolized AAV-CFTR for treatment of cystic fibrosis: A Randomized placebo-controlled phase 2B trial
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DOI：
10.1089/hum.2007.022
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发表时间：
2007-08-01
影响因子：
4.2
通讯作者：
Heald, Alison E.
中科院分区：
文献类型：
--
作者：
Moss, Richard B.;Milla, Carlos;Heald, Alison E.
先前的研究已经证明，将编码完整的人囊性纤维化跨膜调节因子（CFTR）cDNA（tgAAVCF）的重组腺相关病毒（AAV）载体递送至患有囊性纤维化（CF）的受试者的鼻、窦和肺是安全的并且耐受良好。在间隔30天的三个剂量的雾化tgAAVCF或安慰剂的小型随机双盲研究中，在早期时间点观察到肺功能和诱导痰白细胞介素8（IL-8）水平的令人鼓舞但非显著的趋势。这项更大规模的研究是为了验证这些趋势。102名12岁及以上的轻度至中度囊性纤维化受试者（1秒用力呼气流量[FEV 1]：60%预测值）被随机分配至两个雾化剂量的1 × 10（13）DNA酶抗性tgAAVCF颗粒（n = 51）或匹配的安慰剂（n = 51），间隔30天给药。尽管tgAAVCF耐受性良好，但该研究未达到其主要疗效终点，即与安慰剂相比，tgAAVCF初始给药后30天FEV 1的统计学显著改善。两个治疗组的肺功能、诱导痰生物标志物或抗生素使用天数随时间的变化无显著差异。因此，重复剂量的雾化tgAAVCF是安全的并且耐受性良好，但是随着时间的推移没有导致肺功能的显著改善。由于基因转移是纠正导致CF疾病的潜在遗传缺陷的最简单、最基本的方法，因此有必要进一步研究以开发用于治疗CF的有效基因转移剂。
Previous studies have demonstrated that delivery of a recombinant adeno-associated virus ( AAV) vector encoding the complete human cystic fibrosis transmembrane regulator ( CFTR) cDNA ( tgAAVCF) to the nose, sinus, and lungs of subjects with cystic fibrosis ( CF) was safe and well tolerated. In a small randomized, double-blind study of three doses of aerosolized tgAAVCF or placebo at 30-day intervals, encouraging but nonsignificant trends in pulmonary function and induced sputum interleukin 8 ( IL-8) levels were seen at early time points. This larger study was conducted to verify these trends. One hundred and two subjects aged 12 years and older with mild-to-moderate cystic fibrosis ( forced expiratory flow in 1 sec [ FEV1] : 60% predicted) were randomized to two aerosolized doses of 1 x 10(13) DNase-resistant particles of tgAAVCF ( n = 51) or matching placebo ( n = 51) administered 30 days apart. Although tgAAVCF was well tolerated, the study did not meet its primary efficacy end point of statistically significant improvement in FEV1 30 days after initial administration of tgAAVCF compared with placebo. There were no significant differences in spirometric lung function over time, induced sputum biologic markers, or days of antibiotic use in either treatment group. Thus repeated doses of aerosolized tgAAVCF were safe and well tolerated, but did not result in significant improvement in lung function over time. Because gene transfer is the simplest, most basic way to correct the underlying genetic defect that leads to disease in CF, further research is warranted to develop an effective gene transfer agent for the treatment of CF.