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Dual FKRP/FST gene therapy normalizes ambulation, increases strength, decreases pathology, and amplifies gene expression in LGMDR9 mice.
- Source :
-
Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2024 Aug 07; Vol. 32 (8), pp. 2604-2623. Date of Electronic Publication: 2024 Jun 22. - Publication Year :
- 2024
-
Abstract
- Recent clinical studies of single gene replacement therapy for neuromuscular disorders have shown they can slow or stop disease progression, but such therapies have had little impact on reversing muscle disease that was already present. To reverse disease in patients with muscular dystrophy, new muscle mass and strength must be rebuilt at the same time that gene replacement prevents subsequent disease. Here, we show that treatment of FKRP <subscript>P448L</subscript> mice with a dual FKRP/FST gene therapy packaged into a single adeno-associated virus (AAV) vector can build muscle strength and mass that exceed levels found in wild-type mice and can induce normal ambulation endurance in a 1-h walk test. Dual FKRP/FST therapy also showed more even increases in muscle mass and amplified muscle expression of both genes relative to either single gene therapy alone. These data suggest that treatment with single AAV-bearing dual FKRP/FST gene therapies can overcome loss of ambulation by improving muscle strength at the same time it prevents subsequent muscle damage. This design platform could be used to create therapies for other forms of muscular dystrophy that may improve patient outcomes.<br />Competing Interests: Declaration of interests P.T.M. has financial conflicts of interest with Sarepta Therapeutics and Genosera Inc. A patent has been filed on this technology.<br /> (Copyright © 2024 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Mice
Gene Expression
Walking
Humans
Gene Expression Regulation
Genetic Therapy methods
Muscle Strength genetics
Dependovirus genetics
Genetic Vectors genetics
Genetic Vectors administration & dosage
Pentosyltransferases genetics
Pentosyltransferases metabolism
Muscle, Skeletal metabolism
Muscle, Skeletal pathology
Disease Models, Animal
Subjects
Details
- Language :
- English
- ISSN :
- 1525-0024
- Volume :
- 32
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Molecular therapy : the journal of the American Society of Gene Therapy
- Publication Type :
- Academic Journal
- Accession number :
- 38910327
- Full Text :
- https://doi.org/10.1016/j.ymthe.2024.06.028