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Development of Utrophin Site Blocking Oligos (SBOs) to Treat Duchenne Muscular Dystrophy (DMD)

开发 Utropin 位点封闭寡核苷酸 (SBO) 来治疗杜氏肌营养不良症 (DMD)

基本信息

批准号：
10678195
负责人：
TEJVIR S KHURANA
金额：
$ 49.08万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-18 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10678195
关键词：
3&apos Untranslated Regions Address Affect Animal Model Binding Binding Sites Biological Biological Assay Biology Cells Chemicals Clinical Trials Consultations Development Disease Dose Duchenne muscular dystrophy Dystrophin Exons FDA approved Face Functional disorder Gene Mutation Genes Genetic Diseases Genetic Transcription Head Homologous Gene Human Immunologics In Vitro Lead Legal patent Mediating Messenger RNA MicroRNAs Mus Muscle Muscle Cells Mutation Oligonucleotides Patients Phase Phenotype Physiology Proteins Qualifying RNA Splicing Repression Rodent Schedule Sequence Homology Series Site Specificity Testing Therapeutic Toxic effect Toxicology Transcription Repressor Transgenic Organisms United States National Institutes of Health Up-Regulation Utrophin Validation Viral Vector Virus Walking Western Blotting autosome clinical candidate design disease-causing mutation efficacy evaluation efficacy study gene therapy immunoreaction in vivo induced pluripotent stem cell lead candidate lead optimization male manufacture mdx mouse meetings mouse model nonhuman primate novel therapeutic intervention pharmacokinetics and pharmacodynamics posttranscriptional pre-Investigational New Drug meeting pre-clinical preclinical study programs protein expression response scale up screening small molecule therapy development translational study

项目摘要

Duchenne Muscular Dystrophy (DMD) is a common, fatal, genetic disease estimated to affect 1 in 3500 live- born males. Currently no definitive therapy exists for DMD providing the impetus for urgently developing therapies to address this unmet need. DMD is caused by mutations in the DMD gene leading to an absence of the dystrophin protein. Utrophin (dystrophin-related protein/DRP) is the autosomal homolog of dystrophin sharing extensive sequence similarity and organizational motifs with dystrophin. Utrophin up-regulation can functionally substitute for the missing dystrophin and ameliorate the dystrophic phenotype of the mdx animal model of DMD, providing biological validation of this approach. We and others have shown that important post-transcriptional mechanisms exist that decrease or repress utrophin expression in myofibres, in particular via binding of miRNAs (e.g. miR let-7c) to the 3' untranslated region (UTR) of utrophin. In a series of exciting translational studies, we have demonstrated that blocking miR let-7c mediated interaction with the 3’ UTR of utrophin, using different chemical classes of site blocking oligonucleotides (SBOs), is sufficient to ‘repress the repression’, increase utrophin expression, and rescue the dystrophic phenotype, in vivo. Importantly, our Proof of Concept (POC) for this strategy was obtained using a phosphorodiamidate morpholino oligonucleotide (PMO)-based SBO which has 100% sequence homology to the human utrophin gene, and hence is ideally suited for translational development. In this BPN proposal responding to PAR 21-163, we propose to develop SBO-based utrophin upregulators that are appropriate for entry into clinical trials as a novel therapeutic strategy for DMD.

杜氏肌营养不良症（DMD）是一种常见的、致命的遗传性疾病，估计每3500人中就有1人受到影响