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如何快速向患者提供安全有效的治疗方面发挥着至关重要的作用。我们开发了一种基于气溶胶的成像技术，用于测量气道中的液体吸收，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气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疾病，影响肺、胰腺、肠、鼻窦、皮肤和肝脏。气道液体过度吸收导致脱水分泌物的积累，并显著促进CF肺病的进展。调节气道液体吸收是CF中许多治疗开发努力的共同目标。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颗粒（Tc-SC）。In-DTPA的总清除率将包括粘膜纤毛和吸收组分，而Tc-SC仅通过粘膜纤毛途径清除。因此，放射性药物清除率之间的差异提供了DTPA吸收的测量。我们的初步体外数据直接将DTPA吸收与液体吸收联系起来，并证明了治疗反应。我们的初步体内数据表明CF患者气道中In-DTPA吸收率增加。我们假设DTPA吸收提供了一种可量化的、非侵入性的气道液体吸收测量方法，（a）对CF基因型敏感，（B）独特地识别基本疾病表型并预测疾病严重程度，（c）通过治疗干预进行调节。所有假设都通过体外和体内研究进行了检验。CF患者将大大受益于新的筛查技术的发展，以排名许多正在进行的治疗开发工作。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。我们的技术提供了比目前在肺中可用的任何其他技术更快速的治疗效果评估，并将加速CF新疗法的开发。 公共卫生相关性：用于筛选和评估新药的临床技术在确定如何快速向患者提供安全有效的治疗方面发挥着至关重要的作用。我们已经开发了一种新的基于气溶胶的成像技术，用于测量气道中的液体吸收，可应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在肺中可用的任何其他技术更快速的治疗效果评估，并将加速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.