Imaging Airway Liquid Absorption in Cystic Fibrosis

描述(由申请人提供)：用于筛选和评估新药的临床技术在确定患者能够以多快的速度获得安全有效的治疗方法方面发挥着关键作用。我们开发了一种基于气雾剂的成像技术，用于测量呼吸道的液体吸收，可用于筛选正在开发的治疗囊性纤维化(CF)的新药。我们建议通过一系列呼吸道细胞培养的体外研究和涉及儿童和成人CF患者的体内研究来进一步发展这项技术。CF是一种常染色体隐性遗传病，影响肺、胰腺、肠道、鼻窦、皮肤和肝脏。呼吸道液体过度吸收会导致脱水分泌物的堆积，并在慢性阻塞性肺疾病的进展中起重要作用。调节呼吸道液体吸收是许多慢性阻塞性肺疾病治疗发展的共同目标。我们的成像技术包括吸入两种放射性药物：一种是可吸收的小分子(In-DTPA)，另一种是不可吸收的微粒(TC-SC)。In-DTPA的总清除量将包括粘液纤毛成分和吸收成分，而TC-SC仅通过粘液纤毛途径清除。因此，放射性药物的清除率之间的差异提供了DTPA吸收的测量方法。我们的初步体外数据直接将DTPA吸收与液体吸收联系起来，并证明了治疗效果。我们的初步体内数据显示，CF患者呼吸道中In-DTPA的吸收率增加。所有的假设都通过体外和体内研究进行了检验。Cf患者将从新的筛查技术的开发中受益匪浅，以对许多正在进行的治疗开发工作进行排名。目前可用于评估新疗法的大多数技术都跟踪疾病的后期影响，即使是初步疗效的确定也需要漫长的研究和大量的患者。我们的技术比目前肺部可用的任何其他技术都能更快地评估治疗效果，并将加快CF新疗法的开发。 与公共卫生相关：用于筛选和评估新药的临床技术在确定向患者提供安全有效的治疗方法的速度方面发挥着至关重要的作用。我们开发了一种新的基于气雾剂的成像技术，用于测量呼吸道中的液体吸收，可用于筛选正在开发的治疗囊性纤维化的新药。我们的技术提供了比目前肺部可用的任何其他技术更快速的治疗效果评估，并将加快囊性纤维化新疗法的开发。

DESCRIPTION (provided by applicant): The clinical techniques used to screen and evaluate new medications play a crucial role in determining how quickly safe and effective therapies can be made available to patients. We have developed an aerosol-based imaging technique for measuring liquid absorption in the airways that can be applied to screen new medications being developed to treat cystic fibrosis (CF). We propose to further develop this technique through a series of in vitro studies with airway cell cultures and in vivo studies involving child and adult CF patients. CF is an autosomal recessive disease that affects the lungs, pancreas, intestines, sinuses, skin, and liver. Airway liquid hyper-absorption causes the accumulation of dehydrated secretions and contributes significantly to the progression of CF lung disease. Modulation of airway liquid absorption is a common target of many therapeutic development efforts in CF. Our imaging technique involves the inhalation of two radiopharmaceuticals: one an absorbable small-molecule (In-DTPA) and the other a non-absorbable particle (Tc-SC). The total clearance of In-DTPA will include both mucociliary and absorptive components while Tc-SC is cleared only through the mucociliary route. The difference between the clearance rates of the radiopharmaceuticals therefore provides a measurement of DTPA absorption. Our preliminary in vitro data directly links DTPA absorption to liquid absorption and demonstrates therapeutic response. Our preliminary in vivo data demonstrate increased rates of In-DTPA absorption in the airways of CF patients. We hypothesize that DTPA absorption provides a quantifiable, non-invasive, measurement of airway liquid absorption that (a) is sensitive to CF genotype, (b) uniquely indentifies basic disease phenotype and predicts disease severity, and (c) is modulated by therapeutic interventions. All hypotheses are tested through both in vitro and in vivo studies. CF patients would benefit greatly from the development of new screening techniques to rank the many ongoing therapeutic development efforts. Most techniques currently available to evaluate new therapies track later-stage effects of the disease, and determining even preliminary efficacy can require lengthy studies and large numbers of patients. Our technique provides more rapid evaluation of therapeutic efficacy than any other technique currently available in the lung, and will speed the development of new therapies for CF. PUBLIC HEALTH RELEVANCE: The clinical techniques used to screen and evaluate new medications play a crucial role in determining how quickly safe and effective therapies can be made available to patients. We have developed a new aerosol- based imaging technique for measuring liquid absorption in the airways that can be applied to screen new medications being developed to treat cystic fibrosis. Our technique provides more rapid evaluation of therapeutic efficacy than any other technique currently available in the lung, and will speed the development of new therapies for cystic fibrosis.