Moss Richard B, Rodman David, Spencer L Terry, Aitken Moira L, Zeitlin Pamela L, Waltz David, Milla Carlos, Brody Alan S, Clancy John P, Ramsey Bonnie, Hamblett Nicole, Heald Alison E
Department of Pediatrics, Stanford University, Stanford, CA, USA.
Chest. 2004 Feb;125(2):509-21. doi: 10.1378/chest.125.2.509.
The primary objective was to determine the safety and tolerability of repeated doses of aerosolized adeno-associated serotype 2 vector containing cystic fibrosis transmembrane conductance regulator (CFTR) complementary DNA (cDNA) [tgAAVCF], an adeno-associated virus (AAV) vector encoding the complete human CFTR cDNA. Secondary objectives included evaluation of pulmonary function assessed by spirometry, lung abnormalities by high-resolution CT (HRCT), airway cytokines, vector shedding, serum neutralizing antibody to AAV serotype 2 (AAV2), and gene transfer and expression in a subset of subjects undergoing bronchoscopy with bronchial brushings.
Randomized, double-blind, placebo-controlled, phase II trial.
Eight cystic fibrosis (CF) centers in the United States.
CF patients with mild lung disease, defined as FEV(1) > or =60% predicted.
Subjects were randomized to inhale three aerosolized doses of 1 x 10(13) deoxyribonuclease-resistant particles of tgAAVCF or matching placebo at 30-day intervals using the Pari LC Plus nebulizer (PARI; Richmond, VA).
Of 42 subjects randomized, 20 subjects received at least one dose of tgAAVCF and 17 subjects received placebo. No difference in the pattern of adverse events or laboratory abnormalities was noted between the two treatment groups. Improvements in induced-sputum interleukin-8 (p = 0.03) and FEV(1) (p = 0.04) were observed at day 14 and day 30, respectively, in the group receiving tgAAVCF when compared to those receiving placebo. No significant differences in HRCT scans were noted. Vector shedding in sputum was observed at low levels up to 90 days after the third dose of vector. All subjects receiving tgAAVCF exhibited an increase (by at least fourfold) in serum AAV2-neutralizing antibodies and detectable levels in BAL fluid from five of six treated subjects undergoing BAL. Gene transfer but not gene expression was detected in a subset of six tgAAVCF subjects who underwent bronchoscopy.
Repeat doses of aerosolized tgAAVCF were safe and well tolerated, and resulted in encouraging trends in improvement in pulmonary function in patients with CF and mild lung disease.
主要目的是确定重复剂量雾化吸入含囊性纤维化跨膜传导调节因子（CFTR）互补DNA（cDNA）的腺相关血清型2载体[tgAAVCF，一种编码完整人类CFTR cDNA的腺相关病毒（AAV）载体]的安全性和耐受性。次要目的包括通过肺量计评估肺功能、通过高分辨率CT（HRCT）评估肺部异常、检测气道细胞因子、载体脱落情况、血清抗AAV血清型2（AAV2）中和抗体，以及在一部分接受支气管镜下支气管刷检的受试者中评估基因转移和表达情况。
随机、双盲、安慰剂对照的II期试验。
美国的8个囊性纤维化（CF）中心。
患有轻度肺部疾病的CF患者，定义为第1秒用力呼气容积（FEV₁）≥预测值的60%。
受试者被随机分组，使用Pari LC Plus雾化器（PARI；弗吉尼亚州里士满），每隔30天吸入3次雾化剂量的1×10¹³个抗脱氧核糖核酸酶颗粒的tgAAVCF或匹配的安慰剂。
42名随机分组的受试者中，20名受试者接受了至少一剂tgAAVCF，17名受试者接受了安慰剂。两个治疗组在不良事件模式或实验室异常方面未观察到差异。与接受安慰剂的组相比，接受tgAAVCF的组在第14天和第30天分别观察到诱导痰白细胞介素-8（p = 0.03）和FEV₁（p = 0.04）有所改善。HRCT扫描未发现显著差异。在第三次给予载体后长达90天的时间里，痰中载体脱落水平较低。所有接受tgAAVCF的受试者血清AAV2中和抗体均升高（至少升高四倍），并且在接受支气管肺泡灌洗（BAL）的6名治疗受试者中的5名的BAL液中检测到可检测水平。在6名接受支气管镜检查的tgAAVCF受试者的一个亚组中检测到了基因转移，但未检测到基因表达。
重复剂量雾化吸入tgAAVCF是安全且耐受性良好的，并且在患有轻度肺部疾病的CF患者中，在肺功能改善方面呈现出令人鼓舞的趋势。
