Dose-Dependent Effects of FKRP Gene-Replacement Therapy on Functional Rescue and Longevity in Dystrophic Mice
Muscular dystrophy-dystroglycanopathies (MDDGs) resulting from fukutin-related protein (FKRP) gene mutations are rare disorders that result in a wide spectrum of clinical severity based on the age of onset, the degree of myogenic atrophy, and/or neurologic involvement. There is no cure for any of th...
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doaj-2f4352fc910c49778ffaedc63f1051882020-11-25T00:13:23ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012018-12-0111106120Dose-Dependent Effects of FKRP Gene-Replacement Therapy on Functional Rescue and Longevity in Dystrophic MiceCharles Harvey Vannoy0Victoria Leroy1Qi Long Lu2McColl-Lockwood Laboratory for Muscular Dystrophy Research, Carolinas Medical Center, Atrium Health, Charlotte, NC 28203, USA; Corresponding author: Charles Harvey Vannoy, McColl-Lockwood Laboratory for Muscular Dystrophy Research, Carolinas Medical Center, Atrium Health, Charlotte, NC 28203, USA.McColl-Lockwood Laboratory for Muscular Dystrophy Research, Carolinas Medical Center, Atrium Health, Charlotte, NC 28203, USAMcColl-Lockwood Laboratory for Muscular Dystrophy Research, Carolinas Medical Center, Atrium Health, Charlotte, NC 28203, USA; Corresponding author: Qi Long Lu, McColl-Lockwood Laboratory for Muscular Dystrophy Research, Carolinas Medical Center, Atrium Health, Charlotte, NC 28203, USA.Muscular dystrophy-dystroglycanopathies (MDDGs) resulting from fukutin-related protein (FKRP) gene mutations are rare disorders that result in a wide spectrum of clinical severity based on the age of onset, the degree of myogenic atrophy, and/or neurologic involvement. There is no cure for any of the FKRP-related disorders, and few options are available for symptom management. Herein, we examine the longitudinal effects of a dose-escalation study to evaluate the safety and therapeutic potential of FKRP gene-replacement therapy in a p.P448L (FKRPP448L) mouse model of MDDG. A recombinant adeno-associated virus (AAV) serotype 9 vector expressing human FKRP (AAV9-FKRP) was systemically administered to FKRPP448L mice at 5 weeks of age, when early onset of the disease is evidenced. A comprehensive analysis of protein and gene expression, histopathology, skeletal muscle function, and cardiorespiratory function was performed over short (9-week) and/or long-term (52-week) study periods. Additional studies assessed the impact of FKRP gene-replacement therapy on lifespan at an advanced stage of disease progression. Results indicate that treatment intervention can restore the biochemical defects in a dose-dependent manner, with potential for improvement in the trajectory of disease progression and extension of the expected lifespan. This study supports the initiation of early-stage clinical trials for FKRP-related disorders. Keywords: muscular dystrophy-dystroglycanopathy, fukutin-related protein, gene therapyhttp://www.sciencedirect.com/science/article/pii/S2329050118301001 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Charles Harvey Vannoy Victoria Leroy Qi Long Lu |
spellingShingle |
Charles Harvey Vannoy Victoria Leroy Qi Long Lu Dose-Dependent Effects of FKRP Gene-Replacement Therapy on Functional Rescue and Longevity in Dystrophic Mice Molecular Therapy: Methods & Clinical Development |
author_facet |
Charles Harvey Vannoy Victoria Leroy Qi Long Lu |
author_sort |
Charles Harvey Vannoy |
title |
Dose-Dependent Effects of FKRP Gene-Replacement Therapy on Functional Rescue and Longevity in Dystrophic Mice |
title_short |
Dose-Dependent Effects of FKRP Gene-Replacement Therapy on Functional Rescue and Longevity in Dystrophic Mice |
title_full |
Dose-Dependent Effects of FKRP Gene-Replacement Therapy on Functional Rescue and Longevity in Dystrophic Mice |
title_fullStr |
Dose-Dependent Effects of FKRP Gene-Replacement Therapy on Functional Rescue and Longevity in Dystrophic Mice |
title_full_unstemmed |
Dose-Dependent Effects of FKRP Gene-Replacement Therapy on Functional Rescue and Longevity in Dystrophic Mice |
title_sort |
dose-dependent effects of fkrp gene-replacement therapy on functional rescue and longevity in dystrophic mice |
publisher |
Elsevier |
series |
Molecular Therapy: Methods & Clinical Development |
issn |
2329-0501 |
publishDate |
2018-12-01 |
description |
Muscular dystrophy-dystroglycanopathies (MDDGs) resulting from fukutin-related protein (FKRP) gene mutations are rare disorders that result in a wide spectrum of clinical severity based on the age of onset, the degree of myogenic atrophy, and/or neurologic involvement. There is no cure for any of the FKRP-related disorders, and few options are available for symptom management. Herein, we examine the longitudinal effects of a dose-escalation study to evaluate the safety and therapeutic potential of FKRP gene-replacement therapy in a p.P448L (FKRPP448L) mouse model of MDDG. A recombinant adeno-associated virus (AAV) serotype 9 vector expressing human FKRP (AAV9-FKRP) was systemically administered to FKRPP448L mice at 5 weeks of age, when early onset of the disease is evidenced. A comprehensive analysis of protein and gene expression, histopathology, skeletal muscle function, and cardiorespiratory function was performed over short (9-week) and/or long-term (52-week) study periods. Additional studies assessed the impact of FKRP gene-replacement therapy on lifespan at an advanced stage of disease progression. Results indicate that treatment intervention can restore the biochemical defects in a dose-dependent manner, with potential for improvement in the trajectory of disease progression and extension of the expected lifespan. This study supports the initiation of early-stage clinical trials for FKRP-related disorders. Keywords: muscular dystrophy-dystroglycanopathy, fukutin-related protein, gene therapy |
url |
http://www.sciencedirect.com/science/article/pii/S2329050118301001 |
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