Pharmacogenomics of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and the Cystic Fibrosis Drug CPX Using Genome Microarray Analysis
Pharmacogenomics of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and the Cystic Fibrosis Drug CPX Using Genome Microarray Analysis
复制标题
使用基因组微阵列分析囊性纤维化跨膜电导调节器 (CFTR) 和囊性纤维化药物 CPX 的药物基因组学
作者：
M. Srivastava;O. Eidelman;H. Pollard
BackgroundCystic fibrosis (CF) is the most common lethal recessive disease affecting children in the U.S. and Europe. For this reason, a number of ongoing attempts are being made to treat the disease either by gene therapy or pharmacotherapy. Several phase 1 gene therapy trials have been completed, and a phase 2 clinical trial with the xanthine drug CPX is in progress. The protein coded by the principal CFTR mutation, ΔF508-CFTR, fails to traffic efficiently from the endoplasmic reticulum to the plasma membrane, and is the pathogenic basis for the missing cAMP-activated plasma membrane chloride channel. CPX acts by binding to the mutant ΔF508-CFTR and correcting the trafficking deficit. CPX also activates mutant CFTR channels. The comparative genomics of wild-type and mutant CFTR has not previously been studied. However, we have hypothesized that the gene expression patterns of human cells expressing mutant or wild-type CFTR might differ, and that a drug such as CPX might convert the mutant gene expression pattern into one more characteristic of wild-type CFTR. To the extent that this is true, a pharmacogenomic profile for such corrective drugs might be deduced that could simplify the process of drug discovery for CF.Materials and MethodsTo test this hypothesis we used cDNA microarrays to study global gene expression in human cells permanently transfected with either wild-type or mutant CFTR. We also tested the effects of CPX on global gene expression when incubated with cells expressing either mutant or wild-type CFTR.ResultsWild-type and mutant ΔF508-CFTR induce distinct and differential changes in cDNA microarrays, significantly affecting up to 5% of the total genes in the array. CPX also induces substantial mutation-dependent and -independent changes in gene expression. Some of these changes involve movement of gene expression in mutant cells in a direction resembling expression in wild-type cells.ConclusionsThese data clearly demonstrate that cDNA array analysis of cystic fibrosis cells can yield useful pharmacogenomic information with significant relevance to both gene and pharmacological therapy. We suggest that this approach may provide a paradigm for genome-based surrogate endpoint testing of CF therapeutics prior to human administration.
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影响因子：
33.6
作者：
D. Gadsby;A. Nairn
通讯作者：
D. Gadsby;A. Nairn
CFPAC-1 细胞中烷基黄嘌呤对氯离子流出的刺激不涉及 A1 腺苷受体。
影响因子：
2.9
作者：
Jacobson,KA;Guay-Broder,C;vanGalen,PJ;Gallo-Rodriguez,C;Melman,N;Jacobson,MA;Eidelman,O;Pollard,HB
通讯作者：
Pollard,HB
影响因子：
56.9
作者：
KEREM, BS;ROMMENS, JM;TSUI, LC
通讯作者：
TSUI, LC
影响因子：
56.9
作者：
COLLINS, FS
通讯作者：
COLLINS, FS
DOI：
10.1073/pnas.94.6.2150
发表时间：
1997-03-18
影响因子：
11.1
作者：
Heller, RA;Schena, M;Davis, RW
通讯作者：
Davis, RW