Apnea Index as an outcome measure of IGF-1 treatment in Rett syndrome

 描述(由申请人提供)：开发许多神经和精神疾病的治疗方法面临的一个主要挑战是普遍缺乏适用于评估整个患者群体和整个患者生命周期的治疗效果的强大生物标记物和结果衡量标准。通常用于这一目的的基于患者的结果衡量标准，如评分表，远不理想，因为它们往往依赖于对具有混合病因的症状的主观和不准确的评估，并且需要相当大的行政和回应(患者/医疗代理人)合作。对症状和体征的临床评估有一些相同的缺点，但额外的局限性可能不是对正在研究的现象的最具代表性的抽样。认识到这一领域重要而被忽视的需求，美国国立卫生研究院的NICHD和NIMH发布了一份资金机会公告PAR-13-213：用于智力和发育障碍患者的治疗试验的结果指标，以鼓励建议开发、验证和/或校准信息性结果指标的R01赠款申请，这些结果指标对这些患者的治疗和药物治疗开发至关重要。在导致智力和发育障碍的疾病谱系中，Rett综合征(RTT)是一种严重的X连锁神经发育障碍，主要影响女性，与编码甲基CpG结合蛋白2的基因MECP2的突变有关。在最近一项针对RTT的胰岛素样生长因子1(IGF-1或mecasermin)的1期试验中，我们通过自动心肺功能测量证明了呼吸暂停的改善。这种呼吸异常是RTT表型的常见和损害方面。目前的R03小额研究资助申请旨在通过对已完成的第一阶段和正在进行的第二阶段IGF-1试验中获得的数据进行分析，提供中央呼吸暂停和病理性呼吸暂停的单独自动化测量，从而进一步完善上述呼吸暂停指数。为了实现这一目标，成立了一个多学科联盟，其中包括一名呼吸神经生物学家(潘博士，Co-Pi)和一名神经发育障碍专业神经学家(Kaufmann博士，Pi)，他们拥有一套独特的专业知识，以利用从原始研究中出现的这一突破性机会。我们的具体目标是对我们的1期/2期IGF-1试验的数据进行从头分析，以便选择和提炼最佳的呼吸暂停指数，作为基于生物标记物的RTT治疗结果的衡量标准。我们最近报告的数据支持我们的假设，即这些新的呼吸措施将允许更好地评估IGF-1和其他RTT治疗的有效性，并为开发神经发育障碍的新型生物标记物类型结果衡量标准奠定基础。这项先导性研究的结果将为未来在专门为此目的提供资金机会的情况下设计一项全面的临床试验提供必要的宝贵初步数据，如S PAR-13-213。

 DESCRIPTION (provided by applicant): A major challenge facing the development of therapeutic treatments of many neurological and psychiatric disorders is the general lack of robust biomarkers and outcome measures that are suitable for assessing treatment efficacy across the entire patient population and throughout the patient's lifespan. Patient-based outcome measures commonly used for this purpose, such as rating scales, are far from ideal because they often rely on subjective and imprecise assessments of symptoms with mixed etiology and require considerable administrative and respondent (patient/medical proxy) cooperation. Clinical assessments of symptoms and signs have some of the same shortcomings, with the additional limitation of perhaps not being the most representative sampling of the phenomenon under study. In recognition of this significant and neglected need in the field, the NICHD and NIMH of the National Institutes of Health have issued a funding opportunity announcement PAR-13-213: Outcome Measures for Use in Treatment Trials for Individuals with Intellectual and Developmental Disabilities to encourage R01 grant applications that propose to develop, validate, and/or calibrate informative outcome measures that are essential for therapy and pharmacological treatment development for these patient populations. Among the spectrum of diseases causing intellectual and developmental disabilities is Rett syndrome (RTT), a severe X-linked neurodevelopmental disorder that mainly affects females and is associated with mutations in MECP2, the gene encoding methyl CpG-binding protein 2. In a recent phase 1 trial of Insulin-like Growth Factor 1 (IGF-1 or mecasermin) in RTT, we demonstrated an improvement in apnea using automated cardiorespiratory measures. Such breathing abnormalities are a common and impairing aspect of the RTT phenotype. The present R03 small research grant application intends to further refine the abovementioned apnea index, by providing separate automated measures of central apnea and pathologic breathholding through analyses of data obtained in the completed phase 1 and ongoing phase 2 IGF-1 trials. Towards this goal, a multidisciplinary consortium comprising a respiratory neurobiologist (Dr. Poon, Co-PI) and a neurologist specialized in neurodevelopmental disorders (Dr. Kaufmann, PI) with a unique set of expertise has been established in order to capitalize on this groundbreaking opportunity emergent from the original studies. Our specific aim is to perform de novo analysis of the data from our phase 1/phase 2 IGF-1 trials in order to select and refine an optimal apnea index as a biomarker-based outcome measure for IGF-1 treatment of RTT. Our recently reported data support our postulate that these novel breathing measures will allow better assessments of the efficacy of IGF-1 and other treatments of RTT, as well as lay the foundation for developing novel biomarker type outcome measures in neurodevelopmental disorders. The results of this pilot study will provide valuable preliminary data necessary for the design of a ful- scale clinical trial in the future under funding opportunities specifically for this purpose, such s PAR-13-213.