FSHD Drug Discovery

项目摘要 项目2：FSHD药物发现 目前没有FSHD的治疗方法，治疗开发是该领域未满足的关键需求。 事实上，直到最近，FSHD的治疗开发几乎不存在。的主要原因 FSHD的致病机制最近才开始变得清晰， 还没有被接受的疾病动物模型。重要的是，我们现在有了一个可行的治疗靶点， FSHD的新细胞和动物模型，包括由瓦格纳、昆克尔和哈珀实验室开发的模型。的 对DUX 4病理生理学的理解的出现和该疾病的新动物模型现在提供了 首次开发新型FSHD靶向疗法的机会。我们认为，一种方法，以FSHD 治疗应该以抑制DUX 4作用为中心，这是项目2的重点。 DUX 4是一种转录因子，可以激活与健康不相容的基因和途径。 肌肉.项目2的目标是开发FSHD药物发现的新方法，重点是抑制 DUX 4蛋白的毒性作用，我们建议在两个水平上实现这一点。在具体目标1中，我们将使用 无偏见的方法，以确定和抑制DUX 4激活的基因和途径，有助于其毒性;和 在具体目标2中，我们将鉴定和表征可以干扰DUX 4蛋白后的化合物， 其毒性作用所需的翻译修饰。因此，我们的方法将通过抑制DUX 4毒性来攻击DUX 4毒性。 蛋白质通过两种不同的机制。使用基于细胞和动物的测试的组合， 本项目的目的是鉴定在FSHD患者中证明长期给药有效的化合物， 关注IND审查

PROJECT SUMMARY Project 2: FSHD Drug Discovery There are currently no treatments for FSHD, and therapy development is a critical unmet need in the field. Indeed, until recently therapeutic development for FSHD has been virtually non-existent. The major reasons for this are that the pathogenic mechanisms underlying FSHD have only recently started becoming clear and there have been no accepted animal models of the disease. Importantly, we now have a viable target for therapy and new cell and animal models of FSHD, including ones developed by the Wagner, Kunkel and Harper labs. The emergence of an understanding of DUX4 pathophysiology and novel animal models of the disease now provide opportunities to develop novel FSHD-targeted therapies for the first time. We believe that one approach to FSHD therapies should center on inhibiting DUX4 action, and this is the focus of Project 2. DUX4 is a transcription factor and may activate genes and pathways that are incompatible with healthy muscle. The goal of Project 2 is develop novel approaches to FSHD drug discovery focused on inhibiting the toxic effects of DUX4 protein, and we propose to accomplish this on two levels. In Specific Aim 1 we will use an unbiased approach to identify and inhibit DUX4-activated genes and pathways that contribute to its toxicity; and in Specific Aim 2, we will identify and characterize compounds that can interfere with DUX4 protein post- translational modifications required for its toxic effects. Thus, our approach will attack DUX4 toxicity by inhibiting the protein through two different mechanisms. Using a combination of cell- and animal-based testing, the overall goal of this Project is to identify compounds that demonstrate efficacy for long-term dosing in FSHD patients, with an eye towards IND review.