In vivo efficacy studies to support the development of DUX4-targeted RNAi therapy for FSHD

体内功效研究支持开发 DUX4 靶向 RNAi 治疗 FSHD

基本信息

批准号：
9299936
负责人：
Scott Q Harper
金额：
$ 38.9万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9299936
关键词：
Address Affect Blood Vessels Clinical Clinical Data Clinical Trials Data Development Disease Event Facioscapulohumeral Muscular Dystrophy Future Generations Genes Goals Heart Human Individual Instruction Knock-in Lead Liver MicroRNAs Modeling Mus Muscle Muscular Dystrophies Myopathy National Institute of Neurological Disorders and Stroke Organ Outcome Pathogenesis Pathogenicity Phase Phenotype RNA RNA Interference RNA Interference Therapy Reporting Safety Sample Size Skeletal Muscle System Testing Therapeutic Therapeutic Uses Tissues Toxic effect Translating Translations Untranslated RNA Vascular System Xenograft procedure adeno-associated viral vector base clinical application design efficacy study gene therapy human disease in vivo mouse model novel overexpression palliative pre-clinical prevent programs prospective safety study standard of care targeted treatment therapy design tissue tropism transcription factor translational approach vector

项目摘要

Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is among the most prevalent muscular dystrophies, affecting 1 in 8,333 to 1 in 20,000 individuals. FSHD was formally classified as a major form of muscular dystrophy in 1954, but the pathogenic events leading to the disease have only recently started coming into focus. Several studies now support an FSHD pathogenesis model involving aberrant expression of the DUX4 gene, which encodes a myotoxic transcription factor. The emergence of DUX4 represented a momentum shift in the FSHD field as it provided an important target for therapy design. Indeed, as FSHD is currently untreatable, developing effective FSHD therapies is a critical need in the field. We hypothesized that an FSHD treatment should center on inhibiting toxic DUX4 expression in skeletal muscles. The objective of this proposal is to develop safe and effective prospective FSHD therapies aimed at reducing toxic DUX4 with RNAi approaches in two novel mouse models of FSHD, using therapeutic non-coding RNAs delivered by adeno- associated viral vectors (AAV). We have designed three Specific Aims to accomplish this objective. Upon completion of these aims, we expect to produce pre-clinical data supporting the translation of a new AAV- based RNAi therapy for FSHD that can be ultimately used for translation toward our goal of clinical application.

常染色体显性骨膜瘤肌肉营养不良（FSHD）是最普遍的肌肉营养不良，影响20,000人中的8,333至1个。 FSHD被正式归类为主要形式 1954年的肌肉营养不良，但导致疾病的致病事件才开始成为焦点。现在的几项研究支持了一个FSHD发病机制模型，涉及异常表达 DUX4基因编码肌毒性转录因子。 Dux4的出现代表 FSHD领域的动量转移为治疗设计提供了重要目标。确实，就像FSHD一样目前不可治疗的，开发有效的FSHD疗法是该领域的关键需求。我们假设了这一点 FSHD治疗应集中于抑制骨骼肌中有毒Dux4的表达。这个目的建议是开发旨在用RNAi减少有毒Dux4的安全有效的前瞻性FSHD疗法在两个新型的FSHD小鼠模型中使用的方法，使用腺样的治疗非编码RNA 相关病毒载体（AAV）。我们设计了三个特定的目标来实现这一目标。之上这些目标的完成，我们希望产生临床前数据，以支持新的AAV-的翻译基于FSHD的基于RNAi治疗，最终可用于转化我们的临床应用目标。