Dataset Information

AAV.Dysferlin Overlap Vectors Restore Function in Dysferlinopathy Animal Models.

ABSTRACT:

Objective

Dysferlinopathies are a family of untreatable muscle disorders caused by mutations in the dysferlin gene. Lack of dysferlin protein results in progressive dystrophy with chronic muscle fiber loss, inflammation, fat replacement, and fibrosis; leading to deteriorating muscle weakness. The objective of this work is to demonstrate efficient and safe restoration of dysferlin expression following gene therapy treatment.

Methods

Traditional gene therapy is restricted by the packaging capacity limit of adeno-associated virus (AAV), however, use of a dual vector strategy allows for delivery of over-sized genes, including dysferlin. The two vector system (AAV.DYSF.DV) packages the dysferlin cDNA utilizing AAV serotype rh.74 through the use of two discrete vectors defined by a 1 kb region of homology. Delivery of AAV.DYSF.DV via intramuscular and vascular delivery routes in dysferlin deficient mice and nonhuman primates was compared for efficiency and safety.

Results

Treated muscles were tested for dysferlin expression, overall muscle histology, and ability to repair following injury. High levels of dysferlin overexpression was shown for all muscle groups treated as well as restoration of functional outcome measures (membrane repair ability and diaphragm specific force) to wild-type levels. In primates, strong dysferlin expression was demonstrated with no safety concerns.

Interpretation

Treated muscles showed high levels of dysferlin expression with functional restoration with no evidence of toxicity or immune response providing proof of principle for translation to dysferlinopathy patients.

SUBMITTER: Sondergaard PC

PROVIDER: S-EPMC4369275 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

AAV.Dysferlin Overlap Vectors Restore Function in Dysferlinopathy Animal Models.

Sondergaard Patricia C PC Griffin Danielle A DA Pozsgai Eric R ER Johnson Ryan W RW Grose William E WE Heller Kristin N KN Shontz Kim M KM Montgomery Chrystal L CL Liu Joseph J Clark Kelly Reed KR Sahenk Zarife Z Mendell Jerry R JR Rodino-Klapac Louise R LR

Annals of clinical and translational neurology 20150120 3

<h4>Objective</h4>Dysferlinopathies are a family of untreatable muscle disorders caused by mutations in the dysferlin gene. Lack of dysferlin protein results in progressive dystrophy with chronic muscle fiber loss, inflammation, fat replacement, and fibrosis; leading to deteriorating muscle weakness. The objective of this work is to demonstrate efficient and safe restoration of dysferlin expression following gene therapy treatment.<h4>Methods</h4>Traditional gene therapy is restricted by the pac ...[more]

PMID: 25815352

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Project description:BackgroundMechanical loading is purported to restore ligament biomechanics post-injury. But this is difficult to corroborate in clinical research when key ligament tissue properties (e.g. strength, stiffness), cannot be accurately measured. We reviewed experimental animal models, to evaluate if post-injury loading restores tissue biomechanics more favourably than immobilisation or unloading. Our second objective was to explore if outcomes are moderated by loading parameters (e.g. nature, magnitude, duration, frequency of loading).MethodsElectronic and supplemental searches were performed in April 2021 and updated in May 2023. We included controlled trials using injured animal ligament models, where at least one group was subjected to a mechanical loading intervention postinjury. There were no restrictions on the dose, time of initiation, intensity, or nature of the load. Animals with concomitant fractures or tendon injuries were excluded. Prespecified primary and secondary outcomes were force/stress at ligament failure, stiffness, laxity/deformation. The Systematic Review Center for Laboratory animal Experimentation tool was used to assess the risk of bias.ResultsThere were seven eligible studies; all had a high risk of bias. All studies used surgically induced injury to the medial collateral ligament of the rat or rabbit knee. Three studies recorded large effects in favour of ad libitum loading postinjury (vs. unloading), for force at failure and stiffness at 12-week follow up. However, loaded ligaments had greater laxity at initial recruitment (vs. unloaded) at 6 and 12 weeks postinjury. There were trends from two studies that adding structured exercise intervention (short bouts of daily swimming) to ad libitum activity further enhances ligament behaviour under high loads (force at failure, stiffness). Only one study compared different loading parameters (e.g. type, frequency); reporting that an increase in loading duration (from 5 to 15 min/day) had minimal effect on biomechanical outcomes.ConclusionThere is preliminary evidence that post-injury loading results in stronger, stiffer ligament tissue, but has a negative effect on low load extensibility. Findings are preliminary due to high risk of bias in animal models, and the optimal loading dose for healing ligaments remains unclear.

Dataset Information

AAV.Dysferlin Overlap Vectors Restore Function in Dysferlinopathy Animal Models.

Objective

Methods

Results

Interpretation

Publications

AAV.Dysferlin Overlap Vectors Restore Function in Dysferlinopathy Animal Models.

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