Biomarkers of the Therapeutic Response

对照临床试验已经确定干扰素β（IFN β）作为复发缓解型MS的重要疾病调节药物，导致3种IFN β产品获得批准。该提案解决了重要的未解决的问题：1）IFN β的治疗机制尚不清楚; 2）没有有效的方法来量化个体患者对IFN β的反应; 3）IFN β治疗反应的生物标志物尚未确定。这一建议是基于这样的假设，即干扰素刺激的蛋白质产物 基因（ISG）介导IFN β在MS中的临床作用。假设ISG的诱导 不同的MS患者和IFN β的个体分子反应解释了个体对治疗的反应。将使用含有约250个ISG的定制cDNA宏阵列来确定对IFN β的主要分子应答，并且应答将与治疗应答和不良事件相关。宏阵列允许在100例RR-MS患者中定量评估ISG，这些患者将在前瞻性设计的临床方案中纵向随访。为了完成这一项目，已经组建了一个具有互补专长的研究小组。首席研究员，博士。 Richard Rudick在MS的结果评估和IFN β研究方面具有丰富的经验。共同研究者Richard Ransohoff博士在评估IFN应答的分子信号方面具有专业知识，并与Rudick博士长期合作。顾问提供统计遗传学、ISG分析和MRI分析方面的专业知识。该项目得到了初步数据的支持，这些数据验证了使用MRI来定义个体对IFN β的反应。 以及证明使用定制的cDNA宏阵列进行MS患者中IFN β应答的离体监测的数据。研究结果将确定IFN β的主要分子反应，阐明其临床作用的机制，并可能阐明MS的致病机制。

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.