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Membrane Stabilization by Modified Steroid Offers a Potential Therapy for Muscular Dystrophy Due to Dysferlin Deficit

Mutations of the DYSF gene leading to reduced dysferlin protein level causes limb girdle muscular dystrophy type 2B (LGMD2B). Dysferlin facilitates sarcolemmal membrane repair in healthy myofibers, thus its deficit compromises myofiber repair and leads to chronic muscle inflammation. An experimental...

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Autores principales: Sreetama, Sen Chandra, Chandra, Goutam, Van der Meulen, Jack H., Ahmad, Mohammad Mahad, Suzuki, Peter, Bhuvanendran, Shivaprasad, Nagaraju, Kanneboyina, Hoffman, Eric P., Jaiswal, Jyoti K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127637/
https://www.ncbi.nlm.nih.gov/pubmed/30166241
http://dx.doi.org/10.1016/j.ymthe.2018.07.021
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author Sreetama, Sen Chandra
Chandra, Goutam
Van der Meulen, Jack H.
Ahmad, Mohammad Mahad
Suzuki, Peter
Bhuvanendran, Shivaprasad
Nagaraju, Kanneboyina
Hoffman, Eric P.
Jaiswal, Jyoti K.
author_facet Sreetama, Sen Chandra
Chandra, Goutam
Van der Meulen, Jack H.
Ahmad, Mohammad Mahad
Suzuki, Peter
Bhuvanendran, Shivaprasad
Nagaraju, Kanneboyina
Hoffman, Eric P.
Jaiswal, Jyoti K.
author_sort Sreetama, Sen Chandra
collection PubMed
description Mutations of the DYSF gene leading to reduced dysferlin protein level causes limb girdle muscular dystrophy type 2B (LGMD2B). Dysferlin facilitates sarcolemmal membrane repair in healthy myofibers, thus its deficit compromises myofiber repair and leads to chronic muscle inflammation. An experimental therapeutic approach for LGMD2B is to protect damage or improve repair of myofiber sarcolemma. Here, we compared the effects of prednisolone and vamorolone (a dissociative steroid; VBP15) on dysferlin-deficient myofiber repair. Vamorolone, but not prednisolone, stabilized dysferlin-deficient muscle cell membrane and improved repair of dysferlin-deficient mouse (B6A/J) myofibers injured by focal sarcolemmal damage, eccentric contraction-induced injury or injury due to spontaneous in vivo activity. Vamorolone decreased sarcolemmal lipid mobility, increased muscle strength, and decreased late-stage myofiber loss due to adipogenic infiltration. In contrast, the conventional glucocorticoid prednisolone failed to stabilize dysferlin deficient muscle cell membrane or improve repair of dysferlinopathic patient myoblasts and mouse myofibers. Instead, prednisolone treatment increased muscle weakness and myofiber atrophy in B6A/J mice—findings that correlate with reports of prednisolone worsening symptoms of LGMD2B patients. Our findings showing improved cellular and pre-clinical efficacy of vamorolone compared to prednisolone and better safety profile of vamorolone indicates the suitability of vamorolone for clinical trials in LGMD2B.
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spelling pubmed-61276372019-09-05 Membrane Stabilization by Modified Steroid Offers a Potential Therapy for Muscular Dystrophy Due to Dysferlin Deficit Sreetama, Sen Chandra Chandra, Goutam Van der Meulen, Jack H. Ahmad, Mohammad Mahad Suzuki, Peter Bhuvanendran, Shivaprasad Nagaraju, Kanneboyina Hoffman, Eric P. Jaiswal, Jyoti K. Mol Ther Original Article Mutations of the DYSF gene leading to reduced dysferlin protein level causes limb girdle muscular dystrophy type 2B (LGMD2B). Dysferlin facilitates sarcolemmal membrane repair in healthy myofibers, thus its deficit compromises myofiber repair and leads to chronic muscle inflammation. An experimental therapeutic approach for LGMD2B is to protect damage or improve repair of myofiber sarcolemma. Here, we compared the effects of prednisolone and vamorolone (a dissociative steroid; VBP15) on dysferlin-deficient myofiber repair. Vamorolone, but not prednisolone, stabilized dysferlin-deficient muscle cell membrane and improved repair of dysferlin-deficient mouse (B6A/J) myofibers injured by focal sarcolemmal damage, eccentric contraction-induced injury or injury due to spontaneous in vivo activity. Vamorolone decreased sarcolemmal lipid mobility, increased muscle strength, and decreased late-stage myofiber loss due to adipogenic infiltration. In contrast, the conventional glucocorticoid prednisolone failed to stabilize dysferlin deficient muscle cell membrane or improve repair of dysferlinopathic patient myoblasts and mouse myofibers. Instead, prednisolone treatment increased muscle weakness and myofiber atrophy in B6A/J mice—findings that correlate with reports of prednisolone worsening symptoms of LGMD2B patients. Our findings showing improved cellular and pre-clinical efficacy of vamorolone compared to prednisolone and better safety profile of vamorolone indicates the suitability of vamorolone for clinical trials in LGMD2B. American Society of Gene & Cell Therapy 2018-09-05 2018-08-27 /pmc/articles/PMC6127637/ /pubmed/30166241 http://dx.doi.org/10.1016/j.ymthe.2018.07.021 Text en © 2018 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Sreetama, Sen Chandra
Chandra, Goutam
Van der Meulen, Jack H.
Ahmad, Mohammad Mahad
Suzuki, Peter
Bhuvanendran, Shivaprasad
Nagaraju, Kanneboyina
Hoffman, Eric P.
Jaiswal, Jyoti K.
Membrane Stabilization by Modified Steroid Offers a Potential Therapy for Muscular Dystrophy Due to Dysferlin Deficit
title Membrane Stabilization by Modified Steroid Offers a Potential Therapy for Muscular Dystrophy Due to Dysferlin Deficit
title_full Membrane Stabilization by Modified Steroid Offers a Potential Therapy for Muscular Dystrophy Due to Dysferlin Deficit
title_fullStr Membrane Stabilization by Modified Steroid Offers a Potential Therapy for Muscular Dystrophy Due to Dysferlin Deficit
title_full_unstemmed Membrane Stabilization by Modified Steroid Offers a Potential Therapy for Muscular Dystrophy Due to Dysferlin Deficit
title_short Membrane Stabilization by Modified Steroid Offers a Potential Therapy for Muscular Dystrophy Due to Dysferlin Deficit
title_sort membrane stabilization by modified steroid offers a potential therapy for muscular dystrophy due to dysferlin deficit
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127637/
https://www.ncbi.nlm.nih.gov/pubmed/30166241
http://dx.doi.org/10.1016/j.ymthe.2018.07.021
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