Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center - Seattle

参议员 Paul D. Wellstone 肌营养不良症专业研究中心 - 西雅图

• 批准号: 10712148
• 负责人: JEFFREY S CHAMBERLAIN
• 金额: $ 174.65万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-07 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712148
• 关键词: Advocacy; Animal Model; Animals; Biological; Characteristics; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Cohort Studies; Data Analyses; Data Set; Development; Disease; Disease Progression; Dose; Dose Limiting; Duchenne muscular dystrophy; Dystrophin; Education; Education and Outreach; Educational Activities; Ensure; Epitopes; Facioscapulohumeral; Facioscapulohumeral Muscular Dystrophy; Family; Fellowship; Foundations; Future; Gene Delivery; Goals; Human; Human Characteristics; Infrastructure; Lead; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Mentors; Methods; Miniature Swine; Molecular; Monitor; Muscular Dystrophies; Myocardium; Online Systems; Patient advocacy; Patients; Performance; Postdoctoral Fellow; Pre-Clinical Model; Production; Reagent; Research; Research Personnel; Research Training; Resource Sharing; Resources; Safety; Skeletal Muscle; Speed; Technology; Testing; Therapeutic; Therapeutic Clinical Trial; Toxic effect; Training; Transgenic Organisms; Translational Research; Variant; Visit; Work; boys; career; cohort; design; effective therapy; gene therapy; graduate student; immunogenicity; improved; intein; inter-institutional; meetings; micro-dystrophin; mouse model; next generation; novel therapeutics; outreach; porcine model; preclinical study; predictive modeling; recruit; success; symposium; therapeutic candidate; therapeutic development; transgene delivery; translational study; vector

Overall Summary/Abstract The major theme of the Seattle Wellstone center is to improve therapeutic approaches to muscular dystrophies by identifying and overcoming the emerging new barriers to successful clinical trials in muscular dystrophies. The specific aims and objectives are to breach the major barriers to successful therapeutic clinical trials in muscular dystrophies in the Northwest and nationwide. Aim 1 (Project 1) will conduct translational and pre-clinical studies of muscular dystrophy gene therapy. Studies in this Aim will (a) identify optimized AAV variants for skeletal and cardiac muscle, modify micro-dystrophin sequences to diminish immunogenicity and increase function, and test split intein vector strategies for delivering more potent dystrophin constructs to skeletal and cardiac muscle; (b) will apply parallel AAV-mediated methods to achieve the suppression of human DUX4 in a mouse model of FSHD and in a large animal porcine model of FSHD, extending the use of similar vector technologies as a general delivery platform for dominant muscular dystrophies and opening new therapeutic opportunities for FSHD. Aim 2 (Project 2) will establish facioscapulohumeral dystrophy clinical trial foundations. Studies in this aim will (a) perform clinical and MRI assessment in a long-term extension of the prior Seattle Wellstone FSHD cohorts and apply newer methods of MRI data analysis to generate a multi-year composite dataset of FSHD disease progression for correlations with disease progression; (b) perform a dose-escalation safety and tolerability study of a therapeutic candidate that will incorporate the most current MRI and molecular characteristics to assess their performance for the design of future clinical trials; and (c) perform functional, MRI, and molecular characterization of a new porcine model of FSHD to determine its utility as a preclinical model for human studies. Aim 3 (Cores A, B, C) will administer, provide resources for scientific research, and train future muscular dystrophy scientific and clinical researchers. The Center cores (Administrative, Scientific Research, and Training) will provide support and oversight of all activities, provide necessary biological resources to achieve the goals of the Center and serve as a national resource, provide training of the next generation of scientific and clinical researchers in muscular dystrophy and conduct outreach and educational activities. Together, these aims will achieve the overall goal to develop the reagents, measurements, clinical trials methods, and clinical trials infrastructures to speed the development of effective therapies for DMD and FSHD, and to bring muscular dystrophy clinical trials and therapies to the families of the Northwest and beyond.

总体总结/摘要 西雅图 Wellstone 中心的主要主题是改进肌肉治疗方法 通过识别和克服肌肉营养不良临床试验成功的新障碍 营养不良。具体目的和目标是突破成功治疗的主要障碍 在西北地区和全国范围内进行肌营养不良症的临床试验。目标 1（项目 1）将进行 肌营养不良症基因治疗的转化和临床前研究。该目标的研究将 (a) 确定 针对骨骼肌和心肌优化的 AAV 变体，修改微肌营养不良蛋白序列以减少 免疫原性和增强功能，并测试分裂内含肽载体策略以提供更有效的 肌营养不良蛋白构建骨骼肌和心肌； (b) 将应用并行 AAV 介导的方法来实现 [0133] 在FSHD小鼠模型和FSHD大型动物猪模型中人DUX4的抑制， 扩展类似载体技术的使用作为优势肌肉的通用传递平台 营养不良并为 FSHD 开辟新的治疗机会。目标 2（项目 2）将建立 面肩肱营养不良临床试验基础。该目标的研究将 (a) 进行临床和 MRI 对之前的西雅图 Wellstone FSHD 队列进行长期扩展评估并应用更新的方法 MRI 数据分析，生成 FSHD 疾病进展的多年综合数据集以获取相关性 随着疾病进展； (b) 对候选治疗药物进行剂量递增安全性和耐受性研究 将结合最新的 MRI 和分子特征来评估其性能 未来临床试验的设计； (c) 对新猪进行功能、MRI 和分子表征 FSHD 模型以确定其作为人类研究临床前模型的效用。目标 3（核心 A、B、C）将 管理、为科学研究提供资源并培训未来的肌营养不良症科学和临床 研究人员。中心核心（行政、科学研究和培训）将提供支持和 监督所有活动，提供必要的生物资源以实现中心的目标并服务 作为国家资源，为下一代肌肉科学和临床研究人员提供培训 营养不良并开展外展和教育活动。这些目标共同实现总体目标 开发试剂、测量、临床试验方法和临床试验基础设施，以加快 开发针对 DMD 和 FSHD 的有效疗法，并开展肌营养不良症临床试验和 为西北及其他地区的家庭提供治疗。

项目成果

Elevated plasma complement components in facioscapulohumeral dystrophy.

面肩肱营养不良患者血浆补体成分升高。

• DOI: 10.1093/hmg/ddab364
• 发表时间: 2022
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Wong,Chao-Jen;Wang,Leo;Holers,VMichael;Frazer-Abel,Ashley;vanderMaarel,SilvèreM;Tawil,Rabi;Statland,JeffreyM;Tapscott,StephenJ;ReSolveNetwork
• 通讯作者: ReSolveNetwork

Gene therapy delivered micro-dystrophins co-localize with transgenic utrophin in dystrophic skeletal muscle fibers.

基因治疗使微肌营养不良蛋白与转基因肌营养不良蛋白共定位于营养不良的骨骼肌纤维中。

• DOI: 10.1016/j.nmd.2024.01.004
• 发表时间: 2024
• 期刊: Neuromuscular disorders : NMD
• 作者: Krishna,Swathy;Piepho,ArdenB;Lake,DanaM;Cumby,LaurelR;Lortz,KaelynK;Lowe,Jeovanna;Chamberlain,JeffreyS;Rafael-Fortney,JillA
• 通讯作者: Rafael-Fortney,JillA

Human DUX4 and porcine DUXC activate similar early embryonic programs in pig muscle cells: implications for preclinical models of FSHD.

人 DUX4 和猪 DUXC 激活猪肌肉细胞中类似的早期胚胎程序：对 FSHD 临床前模型的影响。

• DOI: 10.1093/hmg/ddad021
• 发表时间: 2023
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Nip,Yee;Bennett,SeanR;Smith,AndrewA;Jones,TakakoI;Jones,PeterL;Tapscott,StephenJ
• 通讯作者: Tapscott,StephenJ

Enveloped viruses pseudotyped with mammalian myogenic cell fusogens target skeletal muscle for gene delivery.

用哺乳动物生肌细胞融合剂假型化的包膜病毒以骨骼肌为目标进行基因传递。

• DOI: 10.1016/j.cell.2023.06.025
• 发表时间: 2023
• 期刊: Cell
• 影响因子: 64.5
• 作者: Hindi,SajedahM;Petrany,MichaelJ;Greenfeld,Elena;Focke,LeahC;Cramer,AlyssaAW;Whitt,MichaelA;Khairallah,RamziJ;Ward,ChristopherW;Chamberlain,JeffreyS;Prasad,Vikram;Podbilewicz,Benjamin;Millay,DouglasP
• 通讯作者: Millay,DouglasP

Longitudinal study of MRI and functional outcome measures in facioscapulohumeral muscular dystrophy.

• DOI: 10.1186/s12891-021-04134-7
• 发表时间: 2021-03-10
• 期刊: BMC musculoskeletal disorders
• 影响因子: 2.3
• 作者: Wang LH;Shaw DWW;Faino A;Budech CB;Lewis LM;Statland J;Eichinger K;Tapscott SJ;Tawil RN;Friedman SD
• 通讯作者: Friedman SD