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Systemic Delivery of Dysferlin Overlap Vectors Provides Long-Term Gene Expression and Functional Improvement for Dysferlinopathy

Dysferlinopathies comprise a family of disorders caused by mutations in the dysferlin (DYSF) gene, leading to a progressive dystrophy characterized by chronic muscle fiber loss, fat replacement, and fibrosis. To correct the underlying histopathology and function, expression of full-length DYSF is re...

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Autores principales: Potter, Rachael A., Griffin, Danielle A., Sondergaard, Patricia C., Johnson, Ryan W., Pozsgai, Eric R., Heller, Kristin N., Peterson, Ellyn L., Lehtimäki, Kimmo K., Windish, Hillarie P., Mittal, Plavi J., Albrecht, Douglas E., Mendell, Jerry R., Rodino-Klapac, Louise R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Mary Ann Liebert, Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066196/
https://www.ncbi.nlm.nih.gov/pubmed/28707952
http://dx.doi.org/10.1089/hum.2017.062
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author Potter, Rachael A.
Griffin, Danielle A.
Sondergaard, Patricia C.
Johnson, Ryan W.
Pozsgai, Eric R.
Heller, Kristin N.
Peterson, Ellyn L.
Lehtimäki, Kimmo K.
Windish, Hillarie P.
Mittal, Plavi J.
Albrecht, Douglas E.
Mendell, Jerry R.
Rodino-Klapac, Louise R.
author_facet Potter, Rachael A.
Griffin, Danielle A.
Sondergaard, Patricia C.
Johnson, Ryan W.
Pozsgai, Eric R.
Heller, Kristin N.
Peterson, Ellyn L.
Lehtimäki, Kimmo K.
Windish, Hillarie P.
Mittal, Plavi J.
Albrecht, Douglas E.
Mendell, Jerry R.
Rodino-Klapac, Louise R.
author_sort Potter, Rachael A.
collection PubMed
description Dysferlinopathies comprise a family of disorders caused by mutations in the dysferlin (DYSF) gene, leading to a progressive dystrophy characterized by chronic muscle fiber loss, fat replacement, and fibrosis. To correct the underlying histopathology and function, expression of full-length DYSF is required. Dual adeno-associated virus vectors have been developed, defined by a region of homology, to serve as a substrate for reconstitution of the full 6.5 kb dysferlin cDNA. Previous work studied the efficacy of this treatment through intramuscular and regional delivery routes. To maximize clinical efficacy, dysferlin-deficient mice were treated systemically to target all muscles through the vasculature for efficacy and safety studies. Mice were evaluated at multiple time points between 4 and 13 months post treatment for dysferlin expression and functional improvement using magnetic resonance imaging and magnetic resonance spectroscopy and membrane repair. A systemic dose of 6 × 10(12) vector genomes resulted in widespread gene expression in the muscles. Treated muscles showed a significant decrease in central nucleation, collagen deposition, and improvement of membrane repair to wild-type levels. Treated gluteus muscles were significantly improved compared to placebo-treated muscles and were equivalent to wild type in volume, intra- and extramyocellular lipid accumulation, and fat percentage using magnetic resonance imaging and magnetic resonance spectroscopy. Dual-vector treatment allows for production of full-length functional dysferlin with no toxicity. This confirms previous safety data and validates translation of systemic gene delivery for dysferlinopathy patients.
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spelling pubmed-60661962018-07-31 Systemic Delivery of Dysferlin Overlap Vectors Provides Long-Term Gene Expression and Functional Improvement for Dysferlinopathy Potter, Rachael A. Griffin, Danielle A. Sondergaard, Patricia C. Johnson, Ryan W. Pozsgai, Eric R. Heller, Kristin N. Peterson, Ellyn L. Lehtimäki, Kimmo K. Windish, Hillarie P. Mittal, Plavi J. Albrecht, Douglas E. Mendell, Jerry R. Rodino-Klapac, Louise R. Hum Gene Ther Research Articles Dysferlinopathies comprise a family of disorders caused by mutations in the dysferlin (DYSF) gene, leading to a progressive dystrophy characterized by chronic muscle fiber loss, fat replacement, and fibrosis. To correct the underlying histopathology and function, expression of full-length DYSF is required. Dual adeno-associated virus vectors have been developed, defined by a region of homology, to serve as a substrate for reconstitution of the full 6.5 kb dysferlin cDNA. Previous work studied the efficacy of this treatment through intramuscular and regional delivery routes. To maximize clinical efficacy, dysferlin-deficient mice were treated systemically to target all muscles through the vasculature for efficacy and safety studies. Mice were evaluated at multiple time points between 4 and 13 months post treatment for dysferlin expression and functional improvement using magnetic resonance imaging and magnetic resonance spectroscopy and membrane repair. A systemic dose of 6 × 10(12) vector genomes resulted in widespread gene expression in the muscles. Treated muscles showed a significant decrease in central nucleation, collagen deposition, and improvement of membrane repair to wild-type levels. Treated gluteus muscles were significantly improved compared to placebo-treated muscles and were equivalent to wild type in volume, intra- and extramyocellular lipid accumulation, and fat percentage using magnetic resonance imaging and magnetic resonance spectroscopy. Dual-vector treatment allows for production of full-length functional dysferlin with no toxicity. This confirms previous safety data and validates translation of systemic gene delivery for dysferlinopathy patients. Mary Ann Liebert, Inc. 2018-07-01 2018-07-01 /pmc/articles/PMC6066196/ /pubmed/28707952 http://dx.doi.org/10.1089/hum.2017.062 Text en © Rachael A. Potter et al. 2017; Published by Mary Ann Liebert, Inc. This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Potter, Rachael A.
Griffin, Danielle A.
Sondergaard, Patricia C.
Johnson, Ryan W.
Pozsgai, Eric R.
Heller, Kristin N.
Peterson, Ellyn L.
Lehtimäki, Kimmo K.
Windish, Hillarie P.
Mittal, Plavi J.
Albrecht, Douglas E.
Mendell, Jerry R.
Rodino-Klapac, Louise R.
Systemic Delivery of Dysferlin Overlap Vectors Provides Long-Term Gene Expression and Functional Improvement for Dysferlinopathy
title Systemic Delivery of Dysferlin Overlap Vectors Provides Long-Term Gene Expression and Functional Improvement for Dysferlinopathy
title_full Systemic Delivery of Dysferlin Overlap Vectors Provides Long-Term Gene Expression and Functional Improvement for Dysferlinopathy
title_fullStr Systemic Delivery of Dysferlin Overlap Vectors Provides Long-Term Gene Expression and Functional Improvement for Dysferlinopathy
title_full_unstemmed Systemic Delivery of Dysferlin Overlap Vectors Provides Long-Term Gene Expression and Functional Improvement for Dysferlinopathy
title_short Systemic Delivery of Dysferlin Overlap Vectors Provides Long-Term Gene Expression and Functional Improvement for Dysferlinopathy
title_sort systemic delivery of dysferlin overlap vectors provides long-term gene expression and functional improvement for dysferlinopathy
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066196/
https://www.ncbi.nlm.nih.gov/pubmed/28707952
http://dx.doi.org/10.1089/hum.2017.062
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