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Mol Ther. 2018 Sep 5;26(9):2231-2242. doi: 10.1016/j.ymthe.2018.07.021. Epub 2018 Aug 27.

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

Author information

1
Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC 20010, USA.
2
Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC 20010, USA; Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Binghamton University, Binghamton, NY 13902, USA.
3
Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC 20010, USA; Department of Genomics and Precision Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC 20010, USA. Electronic address: jkjaiswal@cnmc.org.

Abstract

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.

KEYWORDS:

LGMD2B; VBP15; dysferlinopathy; glucocorticoid; inflammation; membrane lipids; membrane repair; muscle injury; steroid

PMID:
30166241
PMCID:
PMC6127637
[Available on 2019-09-05]
DOI:
10.1016/j.ymthe.2018.07.021
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