Center of Research Translation in Muscular Dystrophy Therapeutic Development

肌营养不良症治疗开发研究翻译中心

• 批准号: 10016996
• 负责人: KEVIN M FLANIGAN
• 金额: $ 141.75万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-14 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10016996
• 关键词: Address; Animal Model; Basic Science; Biological Markers; Cells; Child; Clinic; Clinical; Clinical Trials; Data; Development; Disease; Doctor of Philosophy; Duchenne muscular dystrophy; Dystrophin; Enzymes; Exons; Facioscapulohumeral Muscular Dystrophy; Fibroblasts; Funding; GDF8 gene; Gene Transfer; Genes; Goals; Human; Innovative Therapy; Internal Ribosome Entry Site; Intramuscular; Knowledge; Limb structure; Merosin-Deficient Congenital Muscular Dystrophy 1A; Mission; Modeling; Molecular; Muscle; Muscular Dystrophies; Mutation; Myoblasts; Myopathy; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Ohio; Other Genetics; Pathogenesis; Patients; Pediatric Hospitals; Polypeptide N-acetylgalactosaminyltransferase; Preclinical Testing; Principal Investigator; Process; Production; Protein Isoforms; Quality of life; RNA Interference; RNA Splicing; Research; Research Institute; Research Personnel; Research Project Grants; Resources; Ribosomes; Sampling; Serum; Skeletal Muscle; Testing; Tetanus Helper Peptide; Therapeutic; Therapeutic Uses; Translating; Translational Research; Translations; United States National Institutes of Health; Universities; Untranslated RNA; Viral Vector; Work; adeno-associated viral vector; base; bench to bedside; boys; design; dystrophinopathy; effective therapy; exon skipping; experience; first-in-human; gene therapy; glycosylation; human disease; improved; industry partner; interest; muscle form; novel; novel strategies; novel therapeutics; overexpression; pre-clinical; preclinical development; programs; protein expression; research and development; therapeutic development; therapy development; transcription factor; transdifferentiation; type 1a limb girdle muscular dystrophy; vector

Overall CORT Abstract The Center for Gene Therapy at The Research Institute of Nationwide Children's Hospital (RINCH) has a dedicated translational program that targets the muscular dystrophies, with a particular longstanding interest in developing meaningful therapies for the most common forms, including Duchenne muscular dystrophy (DMD) and facioscapulohumeral muscular dystrophy (FSHD). Our Center's goals include unraveling disease pathogenesis and developing new treatment paradigms that can be translated from the bench to the bedside, and under this CORT proposal we seek to accelerate this translational process. Project 1 (PI, Paul Martin, PhD) seeks extend a therapy now entering trials in DMD to other forms of muscular dystrophy, by applying the overexpression of Galgt2, an enzyme that alters skeletal muscle glycosylation to boost the expression of proteins that ameliorate disease. Project 2 (PI, Scott Harper, PhD) explores novel approaches to modulating the expression of the DUX4 gene to treat the relatively common and debilitating FSHD. Project 3 (PI, Kevin Flanigan, MD) seeks to rapidly translate a newly discovered mechanism for dystrophin translational control into meaningful therapy for boys with DMD. All three projects make use of two critical research cores: the Therapeutic Viral Vector Design and Development Research Core (PI, Louise Rodino-Klapac, PhD) and the Muscular Dystrophy Cell and Serum Banking Core (PI, Kim McBride, MD). In addition to the investigators represented here by projects, the proposed CORT represents a larger muscle disease research base at the Nationwide Children's and the Ohio State University, for which a well-developed pilot and feasibility program is described. This proposed CORT is consistent with the mission of NIAMS, which has the goal of finding effective treatments for and to improving the quality of life of patients with debilitating forms of muscle disease.

总体CORT 摘要 国立儿童医院研究所基因治疗中心 （RINCH）有一个专门的翻译计划，针对肌肉萎缩症， 特别是对开发针对最常见形式的有意义的疗法的长期兴趣， 包括杜氏肌营养不良症（DMD）和面肩肱肌营养不良症 （FSHD）。我们中心的目标包括揭示疾病的发病机制和开发新的 治疗范例，可以从板凳翻译到床边，并在此 CORT建议我们寻求加速这一转化过程。项目1（PI，Paul Martin， 博士）寻求将一种目前正在DMD中进行试验的疗法扩展到其他形式的肌营养不良症， 通过过度表达Galgt 2，一种改变骨骼肌糖基化的酶， 促进改善疾病的蛋白质的表达。项目2（PI，Scott哈珀，PhD） 探索新的方法来调节DUX 4基因的表达，以治疗相对 常见且使人衰弱的FSHD。项目3（PI，Kevin Flanigan，MD）旨在快速翻译 新发现的肌营养不良蛋白的翻译控制机制成为有意义的治疗， 患有DMD的男孩这三个项目都利用了两个关键的研究核心：治疗性病毒 载体设计和开发研究核心（PI，Louise Rodino-Klapac，博士）和 肌营养不良细胞和血清库核心（PI，Kim McBride，MD）。除了有 研究人员在这里代表的项目，拟议的CORT代表了一个更大的肌肉 国家儿童和俄亥俄州州立大学的疾病研究基地， 良好的试点和可行性方案进行了说明。这个建议的CORT是一致的 NIAMS的使命是寻找有效的治疗方法， 改善肌肉疾病患者的生活质量。

项目成果

Automated immunofluorescence analysis for sensitive and precise dystrophin quantification in muscle biopsies.

• DOI: 10.1111/nan.12785
• 发表时间: 2022-04
• 期刊: NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY
• 影响因子: 5
• 作者: Vetter, Tatyana A.;Nicolau, Stefan;Bradley, Adrienne J.;Frair, Emma C.;Flanigan, Kevin M.
• 通讯作者: Flanigan, Kevin M.

Pre-clinical Safety and Off-Target Studies to Support Translation of AAV-Mediated RNAi Therapy for FSHD.

临床前安全性和脱靶研究，以支持AAV介导的RNAi治疗FSHD的翻译。

• DOI: 10.1016/j.omtm.2017.12.005
• 发表时间: 2018-03-16
• 期刊: Molecular therapy. Methods & clinical development
• 作者: Wallace LM;Saad NY;Pyne NK;Fowler AM;Eidahl JO;Domire JS;Griffin DA;Herman AC;Sahenk Z;Rodino-Klapac LR;Harper SQ
• 通讯作者: Harper SQ

Designed U7 snRNAs inhibit DUX4 expression and improve FSHD-associated outcomes in DUX4 overexpressing cells and FSHD patient myotubes.

• DOI: 10.1016/j.omtn.2020.12.004
• 发表时间: 2021-03-05
• 期刊: Molecular therapy. Nucleic acids
• 作者: Rashnonejad A;Amini-Chermahini G;Taylor NK;Wein N;Harper SQ
• 通讯作者: Harper SQ

rAAVrh74.MCK.GALGT2 Demonstrates Safety and Widespread Muscle Glycosylation after Intravenous Delivery in C57BL/6J Mice.

rAAVrh74.MCK.GALGT2 在 C57BL/6J 小鼠静脉注射后表现出安全性和广泛的肌肉糖基化。

• DOI: 10.1016/j.omtm.2019.10.005
• 发表时间: 2019
• 期刊: Molecular therapy. Methods & clinical development
• 作者: Zygmunt,DeborahA;Xu,Rui;Jia,Ying;Ashbrook,Anna;Menke,Chelsea;Shao,Guohong;Yoon,JungHae;Hamilton,Sonia;Pisharath,Harshan;Bolon,Brad;Martin,PaulT
• 通讯作者: Martin,PaulT

Direct Reprogramming of Human Fibroblasts into Myoblasts to Investigate Therapies for Neuromuscular Disorders.

将人类成纤维细胞直接重编程为成肌细胞以研究神经肌肉疾病的治疗方法。

• DOI: 10.3791/61991
• 发表时间: 2021
• 期刊: Journal of visualized experiments : JoVE
• 作者: Almeida,CamilaF;Frair,EmmaC;Huang,Nianyuan;Neinast,Reid;McBride,KimL;Weiss,RobertB;Flanigan,KevinM;Wein,Nicolas
• 通讯作者: Wein,Nicolas