Phase I trial of intranasal and endobronchial administration of a recombinant adeno-associated virus serotype 2 (rAAV2)-CFTR vector in adult cystic fibrosis patients: A two-part clinical study

被引:167
作者
Flotte, TR
Zeitlin, PL
Reynolds, TC
Heald, AE
Pedersen, P
Beck, S
Conrad, CK
Brass-Ernst, L
Humphries, M
Sullivan, K
Wetzel, R
Taylor, G
Carter, BJ
Guggino, WB
机构
[1] Univ Florida, Dept Pediat, Gainesville, FL 32610 USA
[2] Univ Florida, Powell Gene Therapy Ctr, Gainesville, FL 32610 USA
[3] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA
[4] Johns Hopkins Univ, Sch Med, Eudowood Div Pediat Resp Sci, Baltimore, MD 21205 USA
[5] Targeted Genet Corp, Seattle, WA 98101 USA
[6] St Christophers Hosp Children, Philadelphia, PA 19102 USA
[7] Stanford Univ, Stanford, CA 94305 USA
[8] Nemours Childrens Clin, Jacksonville, FL 32207 USA
[9] Univ So Calif, Sch Med, Childrens Hosp, Los Angeles, CA 90089 USA
关键词
D O I
10.1089/104303403322124792
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Recombinant adeno-associated serotype 2-based vectors (rAAV2) possess a number of theoretical advantages for cystic fibrosis (CF) gene therapy because they elicit little or no inflammatory response and generally result in stable expression. rAAV2 vectors expressing the cystic fibrosis transmembrane conductance regulator ( CFTR) gene have previously been shown to mediate stable correction of the CF defect in CF bronchial epithelial cells and stable expression of CFTR in rabbit and nonhuman primate models. Here we report the results of the first trial initiated with rAAV in humans, a phase I study in 25 adult and adolescent CF patients with mild to moderate lung disease. Doses of the rAAV-CFTR vector (tgAAVCF) ranging from 3 x 10(1) to 1 x 10(9) replication units (RU), which is equivalent to approximately 6 x 10(4) to 2 x 10(12) DNase resistant particles (DRP), were administered to one side of the nose and to the superior segment of the lower lobe of the right lung. Several adverse events were noted prior to and/or after vector delivery, but most of them appeared to be related to the endogenous CF lung disease or a result of the bronchoscopic procedures. Only one of the serious events was judged to be possibly vector-related ( based on temporal association), and this event was a pulmonary exacerbation very similar to several others experienced by the same subject in the three months preceding vector delivery. Vector shedding was minimal throughout the study, and serum-neutralizing antibodies were detected after vector delivery to subjects in the highest dosage cohorts. Gene transfer as measured by DNA polymerase chain reaction ( PCR) was not observed until cohort 10 in nasal and bronchial epithelia. Sporadic low-level copy numbers suggested gene transfer of anywhere from 0.002 copies per cell up to 0.5 copies per cell was possible; however, DNA PCR was positive in lungs prior to direct dosing suggesting aspiration from the nasal dosing. These data indicate the need for continued evaluation of rAAV-CFTR vectors in additional clinical trials.
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收藏
页码:1079 / 1088
页数:10
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