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.

整体总结/文摘

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

High-throughput, real-time monitoring of engineered skeletal muscle function using magnetic sensing.

• DOI: 10.1177/20417314221122127
• 发表时间: 2022-01
• 期刊: JOURNAL OF TISSUE ENGINEERING
• 影响因子: 8.2
• 作者: Smith, Alec S. T.;Luttrell, Shawn M.;Dupont, Jean-Baptiste;Gray, Kevin;Lih, Daniel;Fleming, Jacob W.;Cunningham, Nathan J.;Jepson, Sofia;Hesson, Jennifer;Mathieu, Julie;Maves, Lisa;Berry, Bonnie J.;Fisher, Elliot C.;Sniadecki, Nathan J.;Geisse, Nicholas A.;Mack, David L.
• 通讯作者: Mack, David L.