Personalized small molecule therapy for severe asthma and cystic fibrosis.

总括 摘要 我们的总体目标是将新的小分子药物转化为针对重症患者的个性化治疗 哮喘和囊性纤维化(CF)。严重的哮喘和慢性萎缩性肺病使阻塞性肺疾病失去作用 是我们治疗开发工作的一个特别重点。在我们的儿科和内科研究中 计划，我们已经开发出针对这两种疾病的潜在有效的小分子疗法。在许多情况下，这些 两种疾病的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条件下都有潜在的活性。然而，现在已经很清楚了 从我们的工作和其他人的工作来看，严重哮喘和CF都存在显著的临床异质性， 而且有特定的患者对每种治疗都会有反应，也有不会有反应。就像大多数药物一样， 无反应的患者实际上可能会受到不必要的治疗的伤害。我们现在有了 开发非侵入性或微创性生物标记物方法来识别应答者和无应答者 到特定的治疗方法。因此，我们建议在该计划的第一阶段使用这些新技术 以确定哪些患者会对我们建议的疗法有反应，哪些患者可能不会有反应。我们将研究目标和 这些疗法的作用机制，包括生化和表观遗传效应。我们还将使用这些 为研究体内和体外治疗之间的相互作用提供信息的数据。在第二个周期中，我们将开始 使用在第一周期中制定的特定临床测试和选择标准的个性化临床试验。许多 重症哮喘和慢性阻塞性肺疾病患者已经从个性化的生物和小分子中受益 最近开发的疗法；我们提议的计划是为了补充这些新的 为了最大限度地降低每位患者的治疗难度和疗效，并最大限度地降低治疗成本，我们提供了多种治疗方法。 我们的多学科计划基于药物开发、临床药物试验、呼吸道氧化还原方面的优势。 化学、细胞培养、细胞生理学和遗传学，因为它们都与严重哮喘和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.