DUX4 inhibition as a therapeutic strategy for FSHD

DUX4 抑制作为 FSHD 的治疗策略

基本信息

批准号：
8442833
负责人：
Scott Q Harper
金额：
$ 17.47万
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：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8442833
关键词：
4q35 Apoptotic Cell Death Chromosomes Clinical Data Code D4Z4 DNA Binding Data Development Disease Dominant-Negative Mutation Engineering Event Exploratory/Developmental Grant Face Facioscapulohumeral Muscular Dystrophy Funding Gene Silencing Genes Goals In Vitro Inborn Genetic Diseases Limb structure Link Mediating MicroRNAs Modeling Molecular Abnormality Mus Muscle Muscular Dystrophies Mutation Myopathy National Institute of Neurological Disorders and Stroke Pathogenesis Patients Positioning Attribute Proteins Publishing RNA Interference Repression Shoulder Testing Therapeutic United States National Institutes of Health Work base effective therapy experience gene therapy improved in vivo innovation mutant novel pre-clinical prevent programs prospective therapeutic target tool transcription factor translational approach vector

项目摘要

DESCRIPTION (provided by applicant): The pathogenic events leading to FSHD have recently started coming into focus. Several studies now support that FSHD is ultimately caused by de-repression of the DUX4 gene, which encodes a pro-apoptotic transcription factor. The emergence of DUX4 as a pathogenic insult in FSHD now makes it possible to begin developing targeted therapies for this currently untreatable disorder. The long-term goal of this proposal is to develop a therapeutic approach for FSHD through DUX4 inhibition. The objective here is to reduce DUX4 expression and activity using RNAi and novel protein therapies. The specific aims of this proposal are expected to demonstrate pre-clinical, in vivo proof-of-principle data on the efficacy of two therapeutic approaches. As such, the specific aims of this proposal are: (1) To develop a DUX4-targeted RNAi-based gene therapy for FSHD, and (2) To develop a dominant negative DUX4 therapy for FSHD. This proposal is significant and innovative because it represents the first steps toward a translational strategy for a targeted FSHD therapy.

描述（由申请人提供）：导致FSHD的致病事件最近开始焦点。现在，几项研究支持FSHD最终是由DUX4基因的抑制引起的，该基因编码了促凋亡的转录因子。现在，DUX4作为FSHD中的致病性侮辱的出现使得可以开始为这种目前不可治疗的疾病开发目标疗法。该提案的长期目标是通过DUX4抑制开发FSHD的治疗方法。这里的目的是使用RNAi和新型蛋白质疗法降低DUX4表达和活性。预计该提案的具体目的将证明有关两种治疗方法有效性的临床前的原则证明。因此，该提案的具体目的是：（1）开发用于FSHD的基于DUX4靶向RNAi的基因疗法，以及（2）为FSHD开发主要的阴性DUX4治疗。该提案具有重要意义和创新性，因为它代表了针对性FSHD治疗的转化策略的第一步。