权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Optimizing and validation of gene therapy vectors to treat limb girdle muscular dystophy

治疗肢带型肌营养不良症的基因治疗载体的优化和验证

基本信息

批准号：
10219370
负责人：
JEFFREY S CHAMBERLAIN
金额：
$ 55.28万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10219370
关键词：
Affect Animal Model Antibodies Area Binding Sites Calpain Cardiac Cardiotoxicity Clinical Trials Code Codon Nucleotides Collaborations Complementary DNA Development Diagnosis Disease Dose Duchenne muscular dystrophy Dystrophin Exercise Tolerance Fiber Gene Delivery Gene Expression Gene Transduction Agent Gene therapy trial Genes Goals Heart Heart Block Human International Knockout Mice Knowledge Limb structure Limb-Girdle Muscular Dystrophies Longitudinal Studies MicroRNAs Modification Mus Muscle Muscle Weakness Muscular Atrophy Muscular Dystrophies Mutation Myocardium Neuromuscular Diseases Outcome Outcome Measure Pathogenesis Patients Peptide Hydrolases Phenotype Physiological Property Proteins Series Skeletal Muscle Testing Therapeutic Therapeutic Effect Therapeutic Intervention Time Toxic effect Transgenes Treatment Efficacy Universities Untranslated Regions Validation Variant Viral Vector Washington Wasting Syndrome Western Blotting Wheelchairs Work adeno-associated viral vector design differential expression experience gene therapy gene therapy clinical trial in vitro testing in vivo laser capture microdissection member micro-dystrophin mini-dystrophin mitochondrial dysfunction mouse model novel overexpression pre-clinical safety testing therapeutic evaluation vector

项目摘要

PROJECT SUMMARY We aim to develop a gene therapy for limb girdle muscular dystrophy type 2A (LGMD2A), an autosomal recessive (AR) muscle wasting disorder due to mutations in CAPN3. LGMD2A is considered to be the most prevalent of the AR LGMDs and yet there is currently no treatment for patients, who are usually wheelchair dependent a decade after diagnosis. We and others have shown that overexpression of CAPN3 can be accomplished in skeletal muscle without toxicity; a finding which makes the feasibility of gene therapy for LGMD2A a realistic goal; however, LGMD2A is unique from most other LGMDs and this fact warrants careful development of gene therapy vectors. One consideration is that CAPN3 cannot be expressed in the heart, due to cardiac toxicity, which is not the case with Duchenne muscular dystrophy and other LGMDs. Although a few pre-clinical, proof of concept studies have successfully accomplished AAV-Capn3 overexpression in mice, there has not been a systematic optimization of any gene therapy construct for humans with LGMD2A, especially one that considers the relative skeletal muscle vs cardiac gene expression issues. Furthermore, because LGMD2A preferentially impacts slow fibers, it is critical that the therapeutic construct that is ultimately carried into clinical trials is optimized for slow fiber expression. Because each patient can only be dosed one time, it is imperative that the construct used for gene delivery is ideal. In this application, we will use an iterative and systematic approach to optimize these vectors. We have assembled an expert, collaborative team with deep experience in the area of regulatory cassettes, AAV vector development and LGMD2A pathogenesis and calpainopathy animal models. The team will work together to generate and test the safety and efficacy of a series of AAV vectors to develop a treatment for LGMD2A. These vectors will be optimized for slow fiber expression while avoiding cardiac toxicity. One team member, Dr. Hauschka, is largely credited with creating the vast majority of regulatory cassettes being used in the current AAV-gene therapy trials for Duchenne muscular dystrophy. Dr. Chamberlain designed and optimized the first micro and mini dystrophins, which formed the basis for all constructs currently in gene therapy clinical trials for DMD. Drs. Spencer and Kramerova generated numerous mouse models that have led to the identification of outcome measures useful for testing therapeutic interventions for LGMD2A. Dr. Cannon, is an internationally known muscle physiologist who will carry out physiological assessments of contractile function. The team will apply their extensive and cumulative knowledge of LGMD2A, AAV vectors, regulatory cassettes and mouse muscle testing to create this gene therapy for LGMD2A.

项目总结