Personalized small molecule therapy for severe asthma and cystic fibrosis.

整体 摘要 我们的总体目标是将新的小分子药物转化为针对重度 哮喘和囊性纤维化（CF）。严重哮喘和CF是致残性阻塞性肺病， 一直是我们治疗开发工作的重点在我们的儿科和内科研究中 通过这些项目，我们已经开发出了潜在有效的小分子疗法。在许多情况下，这些 在这两种疾病中，治疗方法相似或相同。例如，S-亚硝基谷胱甘肽（GSNO）、GSNO-模拟物 化合物和GSNO还原酶抑制剂在这两种情况下都具有潜在活性。然而，现在很清楚， 从我们的工作和其他人的工作来看，严重哮喘和CF两者都存在实质性的临床异质性， 并且有特定的患者会对每种治疗产生反应，也会对每种治疗产生反应。与大多数药物一样， 无反应的患者实际上可能会因不必要的治疗而受到伤害。我们现在已经 开发了无创或微创生物标志物方法，以识别应答者和非应答者 具体的治疗。因此，我们建议在本计划的第一阶段使用这些新技术 以确定哪些患者可能对我们提出的疗法有反应，哪些患者可能对我们提出的疗法没有反应。我们将研究目标， 这些疗法的作用机制，包括生物化学和表观遗传效应。我们还将利用这些 为体外和体内治疗之间相互作用的研究提供信息的数据。在第二个周期，我们将开始 个性化的临床试验，使用特定的临床测试和选择标准，在第一个周期。许多 重度哮喘和CF患者已经从个性化生物和小分子药物中获益 最近开发的疗法;我们提出的计划旨在补充这些新的 为了优化每个患者的治疗的简易性和有效性，并最大限度地降低治疗成本， 我们的多学科计划是基于药物开发，临床药物试验，气道氧化还原 化学、细胞培养、细胞生理学和遗传学，因为它们与严重哮喘和CF有关。

Overall Abstract Our overall goal is to translate new, small molecule drugs into personalized therapies for severe asthma and cystic fibrosis (CF). Severe asthma and CF are disabling obstructive lung diseases that have been a particular focus of our therapeutic development efforts. In our pediatric and internal medicine research programs, we have developed potentially effective small molecule therapies for both. In many cases, these therapies are similar or identical in both diseases. For example, S-nitrosoglutathione (GSNO), GSNO-mimetic compounds and GSNO reductase inhibitors are potentially active in both conditions. However, it is now clear from our work and that of others that there is substantial clinical heterogeneity in both severe asthma and CF, and that there are specific patients who will and will not respond to each treatment. As with most drugs, patients who are non-responders could actually be harmed by unnecessary treatment. We have now developed noninvasive or minimally invasive biomarker approaches to identify responders and non-responders to specific treatments. Therefore, we propose in the first phase of this program to use these novel techniques to identify patients who will and will not likely respond to our proposed therapies. We will study targets and mechanisms of action for these therapies, including biochemical and epigenetic effects. We will also use these data to inform studies of interactions between therapies in vitro and in vivo. In the second cycle, we will begin personalized clinical trials using specific clinical testing and selection criteria developed in the first cycle. Many severe asthma and CF patients are benefitting already from personalized biological and small molecule therapies that have recently been developed; our proposed program is meant to complement these novel therapies in order to optimize the ease and efficacy – and minimize the cost - of treatment for each patient. Our multidisciplinary program is based strengths in drug development, clinical drug trials, airway redox chemistry, cell culture, cell physiology and genetics as they relate both to severe asthma and to CF.