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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...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Mary Ann Liebert, Inc.
2018
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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. |
format | Online Article Text |
id | pubmed-6066196 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Mary Ann Liebert, Inc. |
record_format | MEDLINE/PubMed |
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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