دورية أكاديمية
أعرض في EDS

Systemic delivery of full-length dystrophin in Duchenne muscular dystrophy mice.

التفاصيل البيبلوغرافية
العنوان: Systemic delivery of full-length dystrophin in Duchenne muscular dystrophy mice.
المؤلفون: Zhou Y; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.; Department of Thoracic Surgery, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China., Zhang C; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA., Xiao W; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA., Herzog RW; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA., Han R; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. rh11@iu.edu.
المصدر: Nature communications [Nat Commun] 2024 Jul 21; Vol. 15 (1), pp. 6141. Date of Electronic Publication: 2024 Jul 21.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : Nature Pub. Group
مواضيع طبية MeSH: Dystrophin*/genetics , Dystrophin*/metabolism , Muscular Dystrophy, Duchenne*/genetics , Muscular Dystrophy, Duchenne*/metabolism , Muscular Dystrophy, Duchenne*/therapy , Muscular Dystrophy, Duchenne*/pathology , Genetic Therapy*/methods , Mice, Inbred mdx* , Dependovirus*/genetics , Muscle, Skeletal*/metabolism , Muscle, Skeletal*/pathology , Genetic Vectors*/genetics , Genetic Vectors*/administration & dosage, Animals ; Mice ; Male ; Disease Models, Animal ; Myocardium/metabolism ; Myocardium/pathology ; Sarcolemma/metabolism ; Humans ; Gene Transfer Techniques
مستخلص: Current gene therapy for Duchenne muscular dystrophy (DMD) utilizes adeno-associated virus (AAV) to deliver micro-dystrophin (µDys), which does not provide full protection for striated muscles as it lacks many important functional domains of full-length (FL) dystrophin. Here we develop a triple vector system to deliver FL-dystrophin into skeletal and cardiac muscles. We split FL-dystrophin into three fragments linked to two orthogonal pairs of split intein, allowing efficient assembly of FL-dystrophin. The three fragments packaged in myotropic AAV (MyoAAV4A) restore FL-dystrophin expression in both skeletal and cardiac muscles in male mdx 4cv mice. Dystrophin-glycoprotein complex components are also restored at the sarcolemma of dystrophic muscles. MyoAAV4A-delivered FL-dystrophin significantly improves muscle histopathology, contractility, and overall strength comparable to µDys, but unlike µDys, it also restores defective cavin 4 localization and associated signaling in mdx 4cv heart. Therefore, our data support the feasibility of a mutation-independent FL-dystrophin gene therapy for DMD, warranting further clinical development.
(© 2024. The Author(s).)
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معلومات مُعتمدة: R01HL159900 U.S. Department of Health & Human Services | National Institutes of Health (NIH); R01HL170260 U.S. Department of Health & Human Services | National Institutes of Health (NIH); R21HL163720 U.S. Department of Health & Human Services | National Institutes of Health (NIH); R01HL169976 U.S. Department of Health & Human Services | National Institutes of Health (NIH)
المشرفين على المادة: 0 (Dystrophin)
تواريخ الأحداث: Date Created: 20240721 Date Completed: 20240721 Latest Revision: 20240721
رمز التحديث: 20240722
DOI: 10.1038/s41467-024-50569-6
PMID: 39034316
قاعدة البيانات: MEDLINE
الوصف
تدمد:2041-1723
DOI:10.1038/s41467-024-50569-6