Molecular Genetics of Cystic Fibrosis

描述（由申请人提供）：囊性纤维化（CF）是一种限制生命的液体和电解质运输疾病，影响全球70,000人。CF患者携带每个CF跨膜传导调节（CFTR）基因的功能突变缺失。CFTR编码camp激活的氯离子通道，该通道对于肺气道和胰管粘膜分泌物的适当水化以及维持汗液中氯离子的正确浓度至关重要。最近，随着Kalydeco （VX-770）的成功临床试验，CF的治疗取得了重大进展，Kalydeco是一种增强剂化合物，可增强携带G551D突变（CF等位基因约2-3%）的CFTR的功能，从而降低汗液氯化物浓度（[Cl-]）并改善肺功能测量。Kalydeco的成功促进了许多其他化合物的发展，这些化合物可以纠正突变CFTR的错误折叠形式（“纠正者”），以及其他化合物，可以“增强”CFTR，使其在野生型水平上不进行氯化物传导。我们现在站在能够从根源上治疗CF的门槛上；然而，在向所有CF患者提供分子治疗方面存在重大挑战。首先，CFTR中存在许多不同的错义和帧内缺失突变（n=816），每种突变的临床试验都是不可行的。第二,

DESCRIPTION (provided by applicant): Cystic fibrosis (CF) is a life-limiting disorder of fluid and electrolyte transport affecting 70,000 individuals worldwide. Patients with CF carry loss of function mutations in each CF Transmembrane conductance Regulator (CFTR) gene. CFTR encodes a cAMP-activated chloride channel that is critical for proper hydration of mucous secretions in the pulmonary airways and pancreatic ducts and maintaining the correct concentration of chloride in sweat. Recently, treatment of CF has taken a major step forward with successful clinical trials of Kalydeco (VX-770), a potentiator compound that increases the function of CFTR bearing the G551D mutation (~2-3% of CF alleles) leading to reduced sweat chloride concentration ([Cl-]) and improved lung function measurements. The success of Kalydeco has fostered the development of numerous other compounds that can correct misfolded forms of mutant CFTR ("correctors") and additional compounds that "potentiate" CFTR that does not conduct chloride at wildtype levels. We now stand at the threshold of being able to treat CF at its root cause; however, there are substantial challenges in delivering molecular therapy to all CF patients. First, there are many different missense and in frame deletion mutations in CFTR (n=816) that a clinical trial for each mutation is not feasible. Second, we don't know if transient increase in CFTR function translates into long-term improvement in lung disease, the major cause of mortality in CF. Third, as lung disease in CF proceeds over many years, we need to gauge effectiveness of CFTR-directed treatment using 'short-term' clinical endpoints. Key preliminary observations suggest that we can address each challenge. CF-causing missense and in frame deletion mutations (n = 47) clustered into groups according to their effect on folding and/or chloride conduction of CFTR appear to correspond to corrector or potentiator responsiveness. Analysis of ~23,000 patients in the CFTR2 database (cftr2.org) revealed that CFTR chloride channel function (as % of wildtype) transformed to a logarithmic scale correlates with cross-sectional lung function (r = 0.43; p = 0.002) and with sweat [Cl-] (r = 0.80; p= 1.3 x 10-11). The overall goal of this application is to inform treatment of CF with CFTR-directed therapies by advancing our understanding of the relationship between CFTR function and clinical manifestations. This goal will be achieved by 1) Classifying CF-causing mutations according to their effect on folding and/or conduction to assess their likely response to current and future CFTR-directed therapeutics; 2) Determining the extent to which longitudinal lung function correlates with in vitro CFTR molecular defects and 3) Determining if longitudinal measures of lung function correlate with in vivo CFTR function as measured by sweat [Cl-]. Upon completion of these aims, we will have mined the CFTR2 database and correlated phenotype data with in vitro properties of CFTR mutants to maximize the number of CF patients eligible for CFTR-directed therapy, to estimate the benefit of molecular therapy on long-term lung function in CF patients and to validate the use of sweat gland function to monitor the effectiveness of CFTR-directed treatment.