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Project 1

项目1

基本信息

批准号：
10684170
负责人：
ERIC N Olson
金额：
$ 53.29万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10684170
关键词：
Affect Aging Animal Model Animal Muscular Dystrophy Applications Grants Brain CRISPR/Cas technology Canis familiaris Cell Nucleus Cell model Cessation of life Clinic Clustered Regularly Interspaced Short Palindromic Repeats Collaborations DNA Sequence Alteration Dependovirus Disease Dose Duchenne muscular dystrophy Dystrophin Exercise Exons Funding Gene Expression Profile Gene Mutation Genes Genome Genomic approach Genomics Goals Heart Hot Spot Human Individual Inherited Injury Link Longevity Luciferases Mediating Mus Muscle Muscle Fibers Muscle Weakness Muscle function Muscle satellite cell Muscular Dystrophies Mutation Myoblasts Myocardium Nuclear Oligonucleotides Patients Proteins Reading Frames Reporter Scientist Skeletal Muscle System Technology Therapeutic Time Tissues Translating United States National Institutes of Health Viral Work boys disease-causing mutation exon skipping genome editing in vivo in vivo monitoring mouse model muscular dystrophy mouse model muscular structure mutant mutation correction non-invasive monitor novel therapeutic intervention postnatal premature prevent response single nucleus RNA-sequencing stem cells therapeutic genome editing

项目摘要

Project Summary/Abstract Duchenne muscular dystrophy (DMD) is an inherited X-linked disease caused by mutations in the gene encoding dystrophin, a protein required for muscle fiber integrity. The dystrophin gene is one of the largest human genes and consists of 79 exons. Although there are thousands of individual DMD mutations that have been identified in humans, these mutations are concentrated in hot spot regions of the dystrophin gene. DMD affects approximately 1 in 5,000 boys and is characterized by progressive severe muscle weakness and a shortened lifespan. Despite intense efforts to find cures for DMD through a variety of approaches, including myoblast transfer, viral delivery of dystrophin, and oligonucleotide-mediated exon skipping, there remains no cure for this disease. Our approach is to use CRISPR/Cas9 genomic editing to permanently correct DMD by skipping or reframing the mutant dystrophin exons in postnatal muscle tissue in vivo. We refer to this strategy as Myoediting. This genome editing approach removes the genetic mutation responsible for the disease, allowing for permanent correction of muscle structure and function. We deliver the CRISPR/Cas9 components using an adeno-associated virus-9 (AAV9) delivery system which has been shown to provide robust expression in skeletal muscle, heart and brain, the major tissues affected in DMD patients. To date, we have successfully corrected the dystrophin gene mutation in several DMD animal models having mutations in key hot spot regions of the dystrophin gene. In the previous funding period, we generated several other DMD animals models covering the remaining human hot spot regions and propose to correct these mutations using CRISPR/Cas genomic editing. Although we have made much progress using CRISPR/Cas genomic editing to correct DMD, there remains more work to be done to translate this gene editing therapy to the clinic. The efficiency of delivering the CRISPR/Cas9 components needs to be optimized and questions remain as to the durability of dystrophin expression after correction. Furthermore, since muscle fibers have hundreds of nuclei, we need to understand the occurrence of CRISPR/Cas9 genomic editing at the individual nuclear level. The long-term goal of this project remains to optimize and adapt CRISPR/Cas9-mediated genome editing to postnatal muscle and ultimately to leverage this approach to correct DMD mutations in humans. This project continues to represent a close collaboration between clinicians and basic scientists sharing the common goal of advancing a new therapeutic strategy to permanently cure DMD.

项目总结/文摘