Cargando…
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...
Autores principales: | , , , , , , , , |
---|---|
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 |
_version_ | 1783353516196102144 |
---|---|
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. |
format | Online Article Text |
id | pubmed-6127637 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT sreetamasenchandra membranestabilizationbymodifiedsteroidoffersapotentialtherapyformusculardystrophyduetodysferlindeficit AT chandragoutam membranestabilizationbymodifiedsteroidoffersapotentialtherapyformusculardystrophyduetodysferlindeficit AT vandermeulenjackh membranestabilizationbymodifiedsteroidoffersapotentialtherapyformusculardystrophyduetodysferlindeficit AT ahmadmohammadmahad membranestabilizationbymodifiedsteroidoffersapotentialtherapyformusculardystrophyduetodysferlindeficit AT suzukipeter membranestabilizationbymodifiedsteroidoffersapotentialtherapyformusculardystrophyduetodysferlindeficit AT bhuvanendranshivaprasad membranestabilizationbymodifiedsteroidoffersapotentialtherapyformusculardystrophyduetodysferlindeficit AT nagarajukanneboyina membranestabilizationbymodifiedsteroidoffersapotentialtherapyformusculardystrophyduetodysferlindeficit AT hoffmanericp membranestabilizationbymodifiedsteroidoffersapotentialtherapyformusculardystrophyduetodysferlindeficit AT jaiswaljyotik membranestabilizationbymodifiedsteroidoffersapotentialtherapyformusculardystrophyduetodysferlindeficit |