Imaging Airway Liquid Absorption in Cystic Fibrosis

描述（由申请人提供）：用于筛选和评估新药物的临床技术在决定如何快速安全有效地为患者提供治疗方面起着至关重要的作用。我们已经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）的新药物。我们建议通过一系列气道细胞培养的体外研究和儿童和成人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疾病，可累及肺、胰腺、肠、鼻窦、皮肤和肝脏。气道液体的过度吸收导致脱水分泌物的积累，并对CF肺病的进展起重要作用。气道液体吸收的调节是许多CF治疗开发工作的共同目标。我们的成像技术涉及两种放射性药物的吸入：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的总清除将包括粘纤毛和吸收成分，而Tc-SC仅通过粘纤毛途径清除。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。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显示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、无创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)可通过治疗干预调节。所有的假设都是通过体外和体内研究来检验的。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发展努力。目前可用于评估新疗法的大多数技术都是追踪疾病的后期效果，即使是确定初步疗效也可能需要长期研究和大量患者。我们的技术提供了比目前任何其他肺部可用技术更快速的治疗效果评估，并将加速CF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.