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AAV Mini-dystrophin Vectors for DMD Gene Therapy

用于 DMD 基因治疗的 AAV 微型肌营养不良蛋白载体

基本信息

批准号：
7243361
负责人：
Xiao Xiao
金额：
$ 45.7万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7243361
关键词：
Animal Model Animals Basic Science Biochemical Biological Process Canis familiaris Clinical Clinical Protocols Clinical Research Clinical Trials Collaborations Condition Creatine Kinase Data Duchenne muscular dystrophy Funding Mechanisms Future Gene Delivery Genes Goals Grant Guanosine Monophosphate Immune In Vitro Institution Intramuscular Injections Investigation Isolated limb perfusion Laboratories Lead Methods Molecular Mus Muscle Muscular Dystrophies New Territories Numbers Ohio Operative Surgical Procedures Patients Phase Physiological Procedures Production Protocols documentation Quality Control Recombinants Regulatory Element Research Project Grants Route Running Safety Scientist Series Serotyping Specificity Standards of Weights and Measures Technology Testing Therapeutic Toxicology Transgenic Mice Translational Research Treatment Efficacy United States Food and Drug Administration United States National Institutes of Health Universities Viral adeno-associated viral vector cohort design gene therapy gene therapy clinical trial in vivo mdx mouse mini-dystrophin new technology pre-clinical programs promoter quality assurance size success therapeutic gene transgene expression vector

项目摘要

DESCRIPTION (provided by applicant): The goal of this proposal is to design, test, and produce a recombinant adeno-associated viral (AAV) vector carrying a functional mini-dystrophin gene which will be extensively studied in vivo for therapeutic efficacy as well as long-term safety in animal models. The clinical grade vector will be produced in the final year for a Phase I gene therapy safety trial for Duchenne muscular dystrophy (DMD). This proposal is highly integrated, involving scientists in both basic research and clinical studies, with the objective of generating an optimized AAV vector in five years for a Phase I safety trial in DMD patients. The design, test and production of the gene vectors and the pre-clinical safety studies, as required by FDA, will be carried out at the University of Pittsburgh in collaboration with other institutions. A parallel study that is equally important for the success of the clinical trial, but through a different funding mechanism outside this proposal, will be conducted by a team led by Dr. Jerry R. Mendell at the Ohio State University, where a DMD patient cohort will be characterized at the pathological, immunological and molecular levels for future recruitment. To successfully execute this challenging translational research project, we plan to accomplish five Specific Aims. The first three Aims will be devoted to optimization of mini-dystrophin genes, selection of a small but strong muscle-specific promoter, and the investigation of gene delivery methods. The last two Aims will concentrate on preclinical vector toxicology study and clinical grade AAV vector production under the GMP conditions. The success of this grant will lead to the IND filing and RAC submission of the DMD gene therapy protocol.

描述（由申请人提供）：该提案的目标是设计、测试和生产携带功能性微型肌营养不良蛋白基因的重组腺相关病毒（AAV）载体，其将在体内广泛研究治疗功效以及在动物模型中的长期安全性。临床级载体将在最后一年生产，用于杜氏肌营养不良症（DMD）的I期基因治疗安全性试验。该提案是高度整合的，涉及基础研究和临床研究的科学家，目的是在五年内产生优化的AAV载体，用于DMD患者的I期安全性试验。根据FDA的要求，基因载体的设计、测试和生产以及临床前安全性研究将在匹兹堡大学与其他机构合作进行。一项对临床试验的成功同样重要的平行研究，但通过本提案之外的不同资助机制，将由Jerry R. Mendell博士在俄亥俄州州立大学说，DMD患者队列将在病理学、免疫学和分子水平上进行表征，以备将来招募。为了成功地执行这个具有挑战性的转化研究项目，我们计划实现五个具体目标。前三个目标将致力于微型肌营养不良蛋白基因的优化，选择一个小而强的肌肉特异性启动子，并调查基因传递方法。最后两个目标将集中在临床前载体毒理学研究和GMP条件下的临床级AAV载体生产。这项资助的成功将导致DMD基因治疗方案的IND申请和RAC提交。