Airway epithelial CFTR mRNA expression in cystic fibrosis patients after repetitive administration of a recombinant adenovirus

被引:167
作者
Harvey, BG
Leopold, PL
Hackett, NR
Grasso, TM
Williams, PM
Tucker, AL
Kaner, RJ
Ferris, B
Gonda, I
Sweeney, TD
Ramalingam, R
Kovesdi, I
Shak, S
Crystal, RG
机构
[1] Cornell Univ, Weill Med Coll, New York Presbyterian Hosp, Belfer Gene Therapy Core Facil, New York, NY 10021 USA
[2] Cornell Univ, Weill Med Coll, New York Presbyterian Hosp, Div Pulm & Crit Care Med, New York, NY 10021 USA
[3] GenVec Inc, Rockville, MD 20852 USA
[4] Genentech Inc, San Francisco, CA 94080 USA
关键词
D O I
10.1172/JCI7935
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
引用
收藏
页码:1245 / 1255
页数:11
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