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

Sreetama, Sen Chandra; Chandra, Goutam; Meulen, Jan van der; Ahmad, Mohammad Mahad; Suzuki, Peter; Bhuvanendran, Shivaprasad; Nagaraju, Kanneboyina; Hoffman, Eric P.; Jaiswal, Jyoti K.

doi:10.1016/j.ymthe.2018.07.021

Cited by 50 publications

(63 citation statements)

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“…6,7 Vamorolone is a novel drug that appears to optimize traditional steroidal anti-inflammatory activities: transactivation (gene transcription via GRE-mediated binding of ligand/receptor dimers) is lost; transrepression (NF-κB inhibition anti-inflammatory activity) is retained; physiochemical membrane stabilization properties are improved; and mineralocorticoid receptor activity is changed from agonist to antagonist. [8][9][10][11][12][13] Studies of vamorolone in animal models of chronic inflammatory states, including DMD mouse models, have shown retention of antiinflammatory efficacy and loss of adverse effects compared to prednisolone. 10,12,[14][15][16] The retention of antiinflammatory efficacy and loss of side effects in preclinical models are consistent with vamorolone blocking NF-κBassociated proinflammatory signals as a ligand/receptor monomeric state instead of the traditional molecular models of ligand/receptor dimeric complexes.…”

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confidence: 99%

“…[8][9][10][11][12][13] Studies of vamorolone in animal models of chronic inflammatory states, including DMD mouse models, have shown retention of antiinflammatory efficacy and loss of adverse effects compared to prednisolone. 10,12,[14][15][16] The retention of antiinflammatory efficacy and loss of side effects in preclinical models are consistent with vamorolone blocking NF-κBassociated proinflammatory signals as a ligand/receptor monomeric state instead of the traditional molecular models of ligand/receptor dimeric complexes. 17 A phase 1 study of vamorolone in healthy adult men 18 and a 2-week treatment, 2-week washout, 4-week phase 2a study in patients with DMD 19 showed an improved profile of typical glucocorticoid-like safety concerns as measured by serum biomarkers after 2 weeks of treatment.…”

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Vamorolone trial in Duchenne muscular dystrophy shows dose-related improvement of muscle function

et al. 2019

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ObjectiveTo study vamorolone, a first-in-class steroidal anti-inflammatory drug, in Duchenne muscular dystrophy (DMD). MethodsAn open-label, multiple-ascending-dose study of vamorolone was conducted in 48 boys with DMD (age 4-<7 years, steroid-naive). Dose levels were 0.25, 0.75, 2.0, and 6.0 mg/kg/d in an oral suspension formulation (12 boys per dose level; one-third to 10 times the glucocorticoid dose in DMD). The primary goal was to define optimal doses of vamorolone. The primary outcome for clinical efficacy was time to stand from supine velocity. ResultsOral administration of vamorolone at all doses tested was safe and well tolerated over the 24-week treatment period. The 2.0-mg/kg/d dose group met the primary efficacy outcome of improved muscle function (time to stand; 24 weeks of vamorolone treatment vs natural history controls), without evidence of most adverse effects of glucocorticoids. A biomarker of bone formation, osteocalcin, increased in vamorolone-treated boys, suggesting possible loss of bone morbidities seen with glucocorticoids. Biomarker outcomes for adrenal suppression and insulin resistance were also lower in vamorolone-treated patients with DMD relative to published studies of glucocorticoid therapy. ConclusionsDaily vamorolone treatment suggested efficacy at doses of 2.0 and 6.0 mg/kg/d in an exploratory 24-week open-label study. Classification of evidenceThis study provides Class IV evidence that for boys with DMD, vamorolone demonstrated possible efficacy compared to a natural history cohort of glucocorticoid-naive patients and appeared to be tolerated.

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Vamorolone trial in Duchenne muscular dystrophy shows dose-related improvement of muscle function

et al. 2019

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“…While laser based injury is widely used to assess membrane repair capacity [20,[48][49][50] we determined if other methods of neuronal injury could be affected by rhMG53. We used an assay that mechanically injured N2a cells with glass microbeads.…”

Section: Mg53 Increases the Membrane Repair Capacity Of Cultured Neurmentioning

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Enhancing membrane repair increases regeneration in a sciatic injury model

et al. 2020

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Various injuries to the neural tissues can cause irreversible damage to multiple functions of the nervous system ranging from motor control to cognitive function. The limited treatment options available for patients have led to extensive interest in studying the mechanisms of neuronal regeneration and recovery from injury. Since many neurons are terminally differentiated, by increasing cell survival following injury it may be possible to minimize the impact of these injuries and provide translational potential for treatment of neuronal diseases. While several cell types are known to survive injury through plasma membrane repair mechanisms, there has been little investigation of membrane repair in neurons and even fewer efforts to target membrane repair as a therapy in neurons. Studies from our laboratory group and others demonstrated that mitsugumin 53 (MG53), a muscle-enriched tripartite motif (TRIM) family protein also known as TRIM72, is an essential component of the cell membrane repair machinery in skeletal muscle. Interestingly, recombinant human MG53 (rhMG53) can be applied exogenously to increase membrane repair capacity both in vitro and in vivo. Increasing the membrane repair capacity of neurons could potentially minimize the death of these cells and affect the progression of various neuronal diseases. In this study we assess the therapeutic potential of rhMG53 to increase membrane repair in cultured neurons and in an in vivo mouse model of neurotrauma. We found that a robust repair response exists in various neuronal cells and that rhMG53 can increase neuronal membrane repair both in vitro and in vivo. These findings provide direct evidence of conserved membrane repair responses in neurons and that these repair mechanisms can be targeted as a potential therapeutic approach for neuronal injury.

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“…Vamorolone shows multifunctional properties including anti-inflammatory, membrane stabilization, and mineralocorticoid receptor antagonist activities. [8][9][10] In preclinical studies, 9,[11][12][13][14] vamorolone was a potent inhibitor of the proinflammatory NF-kB pathway, which is the mechanism of anti-inflammatory efficacy that is shared by vamorolone and glucocorticoids. This antiinflammatory mechanism of action has been monitored in human trials and studies through reductions of blood biomarkers (CD23, insulin like growth factor binding protein 2 , interleukin-22-binding protein [IL22BP], MMP12, macrophage-derived chemokine/C-C motif chemokine 22 [MDC/CCL22], and lymphotoxin α1/β2).…”

Section: Vamorolonementioning

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Exposure‐Response Analysis of Vamorolone (VBP15) in Boys With Duchenne Muscular Dystrophy

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et al. 2020

The Journal of Clinical Pharma

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Exposure‐response relationships of vamorolone, a novel dissociative steroidal anti‐inflammatory drug, were investigated in clinical trials in boys with Duchenne muscular dystrophy. Variables were clinical outcome measures, Fridericia‐corrected QT (QTcF) duration, and pharmacodynamic (PD) biomarkers. Exposure metrics were area under the plasma concentration time curve (AUC) and maximum plasma concentration (Cmax), with a sigmoid Emax model applied. Significant improvement in clinical efficacy outcomes was observed after 24 weeks of daily dosing. The primary outcome, time to stand from supine velocity, exhibited the highest sensitivity to vamorolone, with the lowest AUC value providing 50% of maximum effect (E50 = 186 ng·h/mL), followed by time to climb 4 stairs (E50 = 478 ng·h/mL), time to run/walk 10 m (E50 = 1220 ng·h/mL), and 6‐minute walk test (E50 = 1770 ng·h/mL). Week 2 changes of proinflammatory PD biomarkers showed exposure‐dependent decreases. The E50 was 260 ng·h/mL for insulin‐like growth factor‐binding protein 2, 1200 ng·h/mL for matrix metalloproteinase 12, 1260 ng·h/mL for lymphotoxin α1/β2, 1340 ng·h/mL for CD23, 1420 ng·h/mL for interleukin‐22‐binding protein, and 1600 ng·h/mL for macrophage‐derived chemokine/C‐C motif chemokine 22. No relationship was found between QTcF interval changes from baseline and Cmax in week 2 or 24. This analysis showed that improvements in clinical efficacy end points in week 24 and PD biomarkers in week 2 were achieved at typical vamorolone exposure of 2 mg/kg daily dose with a median AUC dose of 6 mg/kg (3651 ng·h/mL), corresponding to approximately 95% of maximum effects for most response variables.

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

Cited by 50 publications

References 48 publications

Vamorolone trial in Duchenne muscular dystrophy shows dose-related improvement of muscle function

Vamorolone trial in Duchenne muscular dystrophy shows dose-related improvement of muscle function

Enhancing membrane repair increases regeneration in a sciatic injury model

Exposure‐Response Analysis of Vamorolone (VBP15) in Boys With Duchenne Muscular Dystrophy

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