Airway epithelial CFTR mRNA expression in cystic fibrosis patients after repetitive administration of a recombinant adenovirus
Airway epithelial CFTR mRNA expression in cystic fibrosis patients after repetitive administration of a recombinant adenovirus
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DOI：
10.1172/jci7935
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发表时间：
1999-11-01
影响因子：
15.9
通讯作者：
Crystal, RG
中科院分区：
文献类型：
--
作者：
Harvey, BG;Leopold, PL;Crystal, RG
我们试图评估 E1(-)、E3(-) 腺病毒 (Ad) 载体 (Ad(GV)CFTR10) 将正常人囊性纤维化跨膜电导调节因子 (CFTR) cDNA 转移至囊性纤维化 (CF) 个体气道上皮的能力。我们通过支气管内喷雾对 7 对 CF 患者进行了 9 个月内以 3 x 10(6) 至 2 x 10(9) 斑块形成单位剂量的 Ad(GV)CFTR10 给药。每个 3 个月的周期，我们在治疗前以及治疗后 3 天和 30 天测量气道上皮细胞中载体衍生的 CFTR mRNA 与内源性 CFTR mRNA。数据表明 (a) 该策略似乎是安全的； (b) 首次给药后，CF气道上皮中载体衍生的CFTR cDNA表达呈剂量依赖性，在较高载体剂量下，内源CFTR mRNA水平大于5%； (c) 表达是短暂的，持续时间少于 30 天； (d)第二次施用可以实现表达，但仅在中间剂量下，并且第三次施用没有观察到表达； (e)重复给药导致的表达逐渐缺乏与全身性抗Ad中和抗体的诱导没有密切相关。 Ad 载体的主要优点是它可以将足够水平的 CFTR cDNA 递送至气道上皮，以便 CFTR 表达保护肺部免受 CF 呼吸道表现的影响。然而，这种令人印象深刻的表达水平与表达时间有限这一具有挑战性的事实有关。尽管这一问题最初可以通过重复施用来克服，但未知的机制最终限制了这种策略，并且进一步的重复施用不会导致重复表达。
We sought to evaluate the ability of an E1(-), E3(-) adenovirus (Ad) vector (Ad(GV)CFTR10) to transfer the normal human cystic fibrosis transmembrane conductance regulator (CFTR) cDNA to the airway epithelium of individuals with cystic fibrosis (CF). We administered Ad(GV)CFTR10 at doses of 3 x 10(6) to 2 x 10(9) plaque-forming units over 9 months by endobronchial spray to 7 pairs of individuals with CF. Each 3-month cycle, we measured vector-derived versus endogenous CFTR mRNA in airway epithelial cells prior to therapy, as well as 3 and 30 days after therapy. The data demonstrate that (a) this strategy appears to be safe; (b) after the first administration, vector-derived CFTR cDNA expression in the CF airway epithelium is dose-dependent, with greater than 5% endogenous CFTR mRNA levels at the higher vector doses; (c) expression is transient, lasting less than 30 days; (d) expression can be achieved with a second administration, but only at intermediate doses, and no expression is observed with the third administration; and (e) the progressive lack of expression with repetitive administration does not closely correlate with induction of systemic anti-Ad neutralizing antibodies. The major advantage of an Ad vector is that it can deliver sufficient levels of CFTR cDNA to the airway epithelium so that CFTR expression protects the lungs from the respiratory manifestations of CF. However, this impressive level of expression is linked to the challenging fact that expression is limited in time. Although this can be initially overcome by repetitive administration, unknown mechanisms eventually limit this strategy, and further repetitive administration does not lead to repetitive expression.