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AAV9-DOK7 gene therapy reduces disease severity in Smn 2B/- SMA model mice.
- Source :
-
Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2020 Sep 10; Vol. 530 (1), pp. 107-114. Date of Electronic Publication: 2020 Jul 30. - Publication Year :
- 2020
-
Abstract
- Spinal Muscular Atrophy (SMA) is an autosomal recessive neuromuscular disease caused by deletions or mutations in the survival motor neuron (SMN1) gene. An important hallmark of disease progression is the pathology of neuromuscular junctions (NMJs). Affected NMJs in the SMA context exhibit delayed maturation, impaired synaptic transmission, and loss of contact between motor neurons and skeletal muscle. Protection and maintenance of NMJs remains a focal point of therapeutic strategies to treat SMA, and the recent implication of the NMJ-organizer Agrin in SMA pathology suggests additional NMJ organizing molecules may contribute. DOK7 is an NMJ organizer that functions downstream of Agrin. The potential of DOK7 as a putative therapeutic target was demonstrated by adeno-associated virus (AAV)-mediated gene therapy delivery of DOK7 in Amyotrophic Lateral Sclerosis (ALS) and Emery Dreyefuss Muscular Dystrophy (EDMD). To assess the potential of DOK7 as a disease modifier of SMA, we administered AAV-DOK7 to an intermediate mouse model of SMA. AAV9-DOK7 treatment conferred improvements in NMJ architecture and reduced muscle fiber atrophy. Additionally, these improvements resulted in a subtle reduction in phenotypic severity, evidenced by improved grip strength and an extension in survival. These findings reveal DOK7 is a novel modifier of SMA.<br />Competing Interests: Declaration of competing interest C.L.L. is the co-founder and Chief Scientific Officer of Shift Pharmaceuticals.<br /> (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Dependovirus genetics
Disease Models, Animal
Gene Deletion
Genetic Therapy methods
Mice, Inbred C57BL
Muscular Atrophy, Spinal pathology
Neuromuscular Junction genetics
Neuromuscular Junction pathology
Severity of Illness Index
Survival of Motor Neuron 1 Protein genetics
Muscle Proteins genetics
Muscular Atrophy, Spinal genetics
Muscular Atrophy, Spinal therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2104
- Volume :
- 530
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Biochemical and biophysical research communications
- Publication Type :
- Academic Journal
- Accession number :
- 32828271
- Full Text :
- https://doi.org/10.1016/j.bbrc.2020.07.031