Biomarkers of the Therapeutic Response

受控临床试验已证实，干扰素β(IFNbeta)是治疗复发缓解型MS的一种重要的疾病修正药物，导致3种IFNbeta产品获得批准。这项建议解决了重要的悬而未决的问题：1)IFNbeta的治疗机制尚不清楚；2)没有经过验证的方法来量化单个患者对IFNbeta的反应；以及3)IFNbeta治疗反应的生物标记物尚未定义。这一建议是基于这样一个假设，即干扰素刺激的蛋白质产物 基因(ISGs)介导IFNβ在MS中的临床效应假设是ISGs的诱导 多发性硬化症患者之间的差异，以及个体对IFNbeta的分子反应解释了个体对治疗的反应。对IFNbeta的主要分子反应将使用包含约250个ISG的定制cDNA微阵列来确定，该反应将与治疗反应和不良事件相关。这些大阵列可以定量评估100名RR-MS患者的ISG，这些患者将在前瞻性设计的临床方案中进行纵向跟踪。已经组建了一支具有互补专业知识的研究小组来完成这一项目。该项目的首席调查员Dr。 Richard Rudick博士在结果评估和IFNbeta研究方面拥有丰富的经验，他是联合研究员Richard Ransohoff博士，在评估干扰素应答的分子信号方面拥有专业知识，并与Rudick博士进行了长期的合作。顾问提供统计遗传学、ISG分析和核磁共振分析方面的专业知识。该项目得到了初步数据的支持，这些数据验证了磁共振成像在个体中定义对IFNbeta的反应 以及使用定制的cDNA宏阵列对多发性硬化症患者的IFNbeta反应进行体外监测的数据。结果将确定对IFNbeta的主要分子反应，阐明其临床效应的机制，并可能阐明MS的发病机制。

Controlled clinical trials have established interferon beta (IFNbeta) as an important disease-modifying drug in relapsing remitting MS, leading to approval for 3 IFNbeta products. This proposal addresses important unresolved issues: 1) Therapeutic mechanisms for IFNbeta are not known; 2) There are no validated methods to quantify the response to IFNbeta in an individual patient; and 3) Biomarkers of the IFNbeta therapeutic response have not been defined. This proposal is based on the assumption that protein products of interferon-stimulated genes (ISGs) mediate clinical effects of IFNbeta in MS. The hypothesis is that induction of ISGs varies between MS patients and that the individual molecular response to IFNbeta accounts for the individual response to treatment. The primary molecular response to IFNbeta will be determined using customized cDNA macroarrays containing approximately 250 ISGs, and the response will be correlated with therapeutic response and adverse events. The macroarrays allow quantitatively assessment of ISGs in 100 patients with RR-MS who will be followed longitudinally in a prospectively designed clinical protocol. A research team with complementary expertise has been assembled to accomplish this project. The principal investigator, Dr. Richard Rudick, has substantial experience with outcomes assessment and IFNbeta studies in MS. The Co-investigator, Dr. Richard Ransohoff, has expertise in assessing molecular signalling in response to IFN and a long working collaboration with Dr. Rudick. Consultants provide expertise in statistical genetics, ISG analysis, and MRI analysis. The project is supported by preliminary data that validates the use of MRI to define response to IFNbeta in individual patients; and data demonstrating use of the customized cDNA macroarray to conduct ex vivo monitoring of IFNbeta responses in MS patients. Results will define the primary molecular responses to IFNbeta, clarify mechanisms of its clinical effects, and may elucidate pathogenic mechanisms in MS.