Validation of a Phenotype Model to Predict Response to Alternative OSA Treatments

项目概要/摘要 阻塞性睡眠呼吸暂停（OSA）是一种常见的疾病，具有许多不利的心血管和 神经认知后果。然而，主要的治疗方法，气道正压通气（PAP），耐受性差- 许多个体都患有这种疾病，因此迫切需要开发新的治疗策略。 许多研究表明，OSA是由几种表型特征的相互作用引起的，包括 小气道，过度敏感的呼吸控制系统，睡眠时咽肌活动减少， 以及对呼吸刺激的过早唤醒。在导致这一持续更新的上一笔赠款中， 我们创造了测量这些性状的方法以及一种模型（称为“表型模型”）， 分析这些特征中的每一个对特定患者的OSA的相对贡献。我们相信这个模型可以 对预测对PAP替代品的反应很有价值。 此时，PAP替代品（口腔器械、手术器械和其他器械，如舌下神经 刺激等）结果不一致，并且没有针对OSA的药物治疗。然而， 呃，现在被认为具有致病作用的呼吸控制和唤醒因素，提供了一个， 潜在的新的（和未经测试的）药理学目标。该补助金的目的是验证预测 OSA表型的能力，以及测试单独的新药物治疗的有效性， 与现有的PAP替代物如口腔矫治器治疗相结合。 在该资助的目标1中，将使用先前资助中开发的方法对患者进行“表型分析”。 然后，我们将在模型上进行实验，例如，我们将用药物治疗这个模型， 控制敏感度和唤醒阈值。这些模拟治疗将产生成功的预测， 失败然后，我们将对患者进行治疗，以查看模型预测是否正确。的 将给予的治疗是乙酰唑胺（用于降低药物控制敏感性）和右佐匹克隆 (for提高唤醒阈值）。这些药物将同时或单独给药。 因此，这项赠款的一个创新组成部分是，我们将联合收割机药物，以最大限度地提高疗效。目的2 将测试表型模型预测口腔矫治器治疗反应的能力。的相同方法 表型分析，然后在模型上模拟治疗以生成治疗预测，然后进行前 将使用实验性给药治疗以观察预测是否正确。预测因素 对口腔矫治器治疗响应仍然很差，因此目标2填补了这一常见替代治疗的重要空白- 我是说。最后，目标3将测试表型模型预测对“三联疗法”（acetazola- Mide +右佐匹克隆+口腔矫正器），我们的初步数据表明，这可能对AP有强大的影响。 nea严重程度在正确的“表型”。这项研究可能会导致令人兴奋的新的管理策略， OSA。

PROJECT SUMMARY/ABSTRACT Obstructive Sleep Apnea (OSA) is a prevalent disorder with a number of adverse cardiovascular and neurocognitive consequences. However, the leading treatment, positive airway pressure (PAP), is poorly toler- ated by many individuals and thus the development new treatment strategies are critically needed. A number of studies indicate that OSA is caused by the interplay of several phenotypic traits, including a small airway, an oversensitive ventilatory control system, decreased pharyngeal muscle activity during sleep, and premature arousals to a respiratory stimulus. In the previous grant leading up to this continuing renewal, we created methods for measuring these traits as well as a model (termed the “phenotype model”) that illus- trates the relative contribution of each of these traits to a particular patient's OSA. We believe this model could be valuable for predicting response to PAP-alternatives. At this time, PAP alternatives (oral appliances, surgery, and other devices such as hypoglossal nerve stimulation, etc.) suffer from inconsistent results, and there is no pharmacological treatment for OSA. Howev- er, respiratory control and arousal factors, which are now recognized as having pathogenic roles, provide po- tential new (and untested) pharmacological targets. The objective of this grant is to validate the predictive power of OSA phenotyping, as well as to test the effectiveness of novel pharmacological treatments alone and in combination with existing PAP alternatives such as oral appliance therapy. In Aim 1 of this grant, patients will be “phenotyped” using the methods developed in the previous grant. We will then perform experiments on the model, e.g., we will treat the model with drugs that change ventilatory control sensitivity and arousal threshold. These simulated treatments will generate a prediction of success or failure. We will then administer the treatments to the patient to see if the model prediction was correct. The treatments that will be given are acetazolamide (for decreasing ventilatory control sensitivity) and eszopiclone (for raising the arousal threshold). These medications will be given simultaneously as well as individually. Thus, an innovative component of this grant is that we will combine medications to maximize efficacy. Aim 2 will test the phenotype model's ability to predict response to oral appliance therapy. The same procedure of phenotyping, followed by simulated treatment on the model to generate a treatment prediction, followed by ex- perimental administration of the treatment to see if the prediction was correct will be used. Predictors of re- sponse to oral appliance therapy remain poor, so Aim 2 fills an important gap in this common alternative treat- ment. Finally, Aim 3 will test the phenotype model's ability to predict response to “triple therapy” (acetazola- mide + eszopiclone + an oral appliance), which our preliminary data suggest can have a powerful effect on ap- nea severity in the right “phenotype”. This research could lead to exciting new management strategies for OSA.