CORRECTION OF THE ION-TRANSPORT DEFECT IN CYSTIC-FIBROSIS TRANSGENIC MICE BY GENE-THERAPY

被引:353
作者
HYDE, SC
GILL, DR
HIGGINS, CF
TREZISE, AEO
MACVINISH, LJ
CUTHBERT, AW
RATCLIFF, R
EVANS, MJ
COLLEDGE, WH
机构
[1] UNIV OXFORD,JOHN RADCLIFFE HOSP,INST MOLEC MED,IMPERIAL CANC RES FUND LABS,OXFORD OX3 9DU,ENGLAND
[2] UNIV CAMBRIDGE,DEPT PHARMACOL,CAMBRIDGE CB2 1QJ,ENGLAND
[3] UNIV CAMBRIDGE,DEPT GENET,CAMBRIDGE CB2 1QR,ENGLAND
[4] UNIV CAMBRIDGE,WELLCOME CRC INST CANC & DEV BIOL,CAMBRIDGE CB2 1QR,ENGLAND
基金
英国惠康基金;
关键词
D O I
10.1038/362250a0
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
CYSTIC fibrosis (CF) is a lethal inherited disorder affecting about 1 in 2,000 Caucasians. The major cause of morbidity is permanent lung damage resulting from ion transport abnormalities in airway epithelia that lead to mucus accumulation and bacterial colonization. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene1 that encodes a cyclic-AMP-regulated chloride channel2,3. Cyclic-AMP-regulated chloride conductances are altered in airway epithelia from CF patients4-6, suggesting that the functional expression of CFTR in the airways of CF patients may be a strategy for treatment. Transgenic mice7-9 With a disrupted cftr gene are appropriate for testing gene therapy protocols. Here we report the use of liposomes to deliver a CFTR expression plasmid to epithelia of the airway and to alveoli deep in the lung, leading to the correction of the ion conductance defects found in the trachea of transgenic (cf/cf) mice. These studies illustrate the feasibility of gene therapy for the pulmonary aspects of CF in humans.
引用
收藏
页码:250 / 255
页数:6
相关论文
共 33 条
[1]   DEMONSTRATION THAT CFTR IS A CHLORIDE CHANNEL BY ALTERATION OF ITS ANION SELECTIVITY [J].
ANDERSON, MP ;
GREGORY, RJ ;
THOMPSON, S ;
SOUZA, DW ;
PAUL, S ;
MULLIGAN, RC ;
SMITH, AE ;
WELSH, MJ .
SCIENCE, 1991, 253 (5016) :202-205
[2]   CALCIUM AND CAMP ACTIVATE DIFFERENT CHLORIDE CHANNELS IN THE APICAL MEMBRANE OF NORMAL AND CYSTIC-FIBROSIS EPITHELIA [J].
ANDERSON, MP ;
WELSH, MJ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1991, 88 (14) :6003-6007
[3]   ACUTE AND LONG-TERM AMILORIDE INHALATION IN CYSTIC-FIBROSIS LUNG-DISEASE - A RATIONAL APPROACH TO CYSTIC-FIBROSIS THERAPY [J].
APP, EM ;
KING, M ;
HELFESRIEDER, R ;
KOHLER, D ;
MATTHYS, H .
AMERICAN REVIEW OF RESPIRATORY DISEASE, 1990, 141 (03) :605-612
[4]   PURIFICATION AND FUNCTIONAL RECONSTITUTION OF THE CYSTIC-FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR (CFTR) [J].
BEAR, CE ;
LI, CH ;
KARTNER, N ;
BRIDGES, RJ ;
JENSEN, TJ ;
RAMJEESINGH, M ;
RIORDAN, JR .
CELL, 1992, 68 (04) :809-818
[5]   NA+ TRANSPORT IN CYSTIC-FIBROSIS RESPIRATORY EPITHELIA - ABNORMAL BASAL RATE AND RESPONSE TO ADENYLATE-CYCLASE ACTIVATION [J].
BOUCHER, RC ;
STUTTS, MJ ;
KNOWLES, MR ;
CANTLEY, L ;
GATZY, JT .
JOURNAL OF CLINICAL INVESTIGATION, 1986, 78 (05) :1245-1252
[6]   ALTERNATE PATHWAYS FOR CHLORIDE CONDUCTANCE ACTIVATION IN NORMAL AND CYSTIC-FIBROSIS AIRWAY EPITHELIAL-CELLS [J].
CHAN, HC ;
GOLDSTEIN, J ;
NELSON, DJ .
AMERICAN JOURNAL OF PHYSIOLOGY, 1992, 262 (05) :C1273-C1283
[7]   DEFECTIVE INTRACELLULAR-TRANSPORT AND PROCESSING OF CFTR IS THE MOLECULAR-BASIS OF MOST CYSTIC-FIBROSIS [J].
CHENG, SH ;
GREGORY, RJ ;
MARSHALL, J ;
PAUL, S ;
SOUZA, DW ;
WHITE, GA ;
ORIORDAN, CR ;
SMITH, AE .
CELL, 1990, 63 (04) :827-834
[8]   DEFECTIVE EPITHELIAL CHLORIDE TRANSPORT IN A GENE-TARGETED MOUSE MODEL OF CYSTIC-FIBROSIS [J].
CLARKE, LL ;
GRUBB, BR ;
GABRIEL, SE ;
SMITHIES, O ;
KOLLER, BH ;
BOUCHER, RC .
SCIENCE, 1992, 257 (5073) :1125-1128
[9]   CYSTIC-FIBROSIS MOUSE WITH INTESTINAL-OBSTRUCTION [J].
COLLEDGE, WH ;
RATCLIFF, R ;
FOSTER, D ;
WILLIAMSON, R ;
EVANS, MJ .
LANCET, 1992, 340 (8820) :680-680
[10]   ABNORMAL APICAL CELL-MEMBRANE IN CYSTIC-FIBROSIS RESPIRATORY EPITHELIUM - AN INVITRO ELECTROPHYSIOLOGIC ANALYSIS [J].
COTTON, CU ;
STUTTS, MJ ;
KNOWLES, MR ;
GATZY, JT ;
BOUCHER, RC .
JOURNAL OF CLINICAL INVESTIGATION, 1987, 79 (01) :80-85