Development of Novel Micro-dystrophins with Enhanced Functionality.
AAV
DMD
Duchenne muscular dystrophy
clinical trials
dystrophin
gene therapy
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581
Informations de publication
Date de publication:
06 03 2019
06 03 2019
Historique:
received:
10
10
2018
revised:
03
01
2019
accepted:
07
01
2019
pmc-release:
06
03
2020
pubmed:
6
2
2019
medline:
18
12
2019
entrez:
6
2
2019
Statut:
ppublish
Résumé
Gene therapies using adeno-associated viral (AAV) vectors have advanced into clinical trials for several diseases, including Duchenne muscular dystrophy (DMD). A limitation of AAV is the carrying capacity (∼5 kb) available for genes and regulatory cassettes (RCs). These size constraints are problematic for the 2.2-Mb dystrophin gene. We previously designed a variety of miniaturized micro-dystrophins (μDys) that displayed significant, albeit incomplete, function in striated muscles. To develop μDys proteins with improved performance, we explored structural modifications of the dystrophin central rod domain. Eight μDys variants were studied that carried unique combinations of between four and six of the 24 spectrin-like repeats present in the full-length protein, as well as various hinge domains. Expression of μDys was regulated by a strong but compact muscle-restricted RC (CK8e) or by the ubiquitously active cytomegalovirus (CMV) RC. Vectors were evaluated by intramuscular injection and systemic delivery to dystrophic mdx
Identifiants
pubmed: 30718090
pii: S1525-0016(19)30005-X
doi: 10.1016/j.ymthe.2019.01.002
pmc: PMC6403485
pii:
doi:
Substances chimiques
Dystrophin
0
Nitric Oxide Synthase
EC 1.14.13.39
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
623-635Subventions
Organisme : NICHD NIH HHS
ID : U54 HD083091
Pays : United States
Organisme : NIAMS NIH HHS
ID : U54 AR065139
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL122332
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007270
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR040864
Pays : United States
Organisme : NIAMS NIH HHS
ID : P50 AR065139
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
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