VBP15, a novel anti‐inflammatory and membrane‐stabilizer, improves muscular dystrophy without side effects

Heier, Christopher R.; Damsker, Jesse M.; Yu, Qing; Dillingham, Blythe C.; Huynh, Tony; Meulen, J. H. van der; Sali, Arpana; Miller, Brittany K.; Phadke, Aditi; Scheffer, Luana; Quinn, James L.; Tatem, Kathleen; Jordan, Sarah; Dadgar, Sherry; Rodriguez, Olga; Albanese, Chris; Calhoun, Michael E.; Gordish‐Dressman, Heather; Jaiswal, Jyoti K.; Connor, Edward; McCall, John M.; Hoffman, Eric P.; Reeves, Erica K.M.; Nagaraju, Kanneboyina

doi:10.1002/emmm.201302621

Cited by 156 publications

(274 citation statements)

References 81 publications

(114 reference statements)

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“…Both in vitro and in vivo data are consistent with this model. Heier et al (35) have found that the net balance of prednisolone treatment increases muscle strength to normal, but at the same time, it stunts the growth of mice, resulting in lower maximal strength, and increases muscle damage in mdx mice. And Bauer et al (36) have also found that prednisolone increases cardiac fibrosis in mdx mice.…”

Section: Discussionmentioning

confidence: 99%

Sulforaphane Attenuates Muscle Inflammation in Dystrophin-deficient mdx Mice via NF-E2-related Factor 2 (Nrf2)-mediated Inhibition of NF-κB Signaling Pathway

Sun

Yang

et al. 2015

Journal of Biological Chemistry

148

109

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Background: Sulforaphane attenuates inflammation in different tissues via activation of Nrf2. Results: Sulforaphane-induced Nrf2 ameliorates muscle inflammation in mdx mice and inhibits NF-B signaling pathway. Conclusion: Sulforaphane-mediated Nrf2 mitigates muscle inflammation in mdx mice via inhibition of NF-B signaling pathway. Significance: Nrf2 may represent a new and promising therapeutic target for dystrophic muscle inflammation.

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Section: Discussionmentioning

confidence: 99%

Sulforaphane Attenuates Muscle Inflammation in Dystrophin-deficient mdx Mice via NF-E2-related Factor 2 (Nrf2)-mediated Inhibition of NF-κB Signaling Pathway

Sun

Yang

et al. 2015

Journal of Biological Chemistry

148

109

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“…Recently, VBP15, an NF-κB inhibitor with high glucocorticoid receptor specificity, has been designed to reduce the side effects typical of steroids. In mdx mice, the oral administration of VBP15 resulted in improvement of the dystrophic phenotype, with less adverse effects compared with prednisone [18].…”

Section: Corticosteroidsmentioning

confidence: 97%

Employment of Microencapsulated Sertoli Cells as a New Tool to Treat Duchenne Muscular Dystrophy

Chiappalupi

Salvadori

Luca

et al. 2017

JFMK

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Duchenne muscular dystrophy (DMD) is a lethal X-linked pathology due to lack of dystrophin and characterized by progressive muscle degeneration, impaired locomotion and premature death. The chronic presence of inflammatory cells, fibrosis and fat deposition are hallmarks of DMD muscle tissue. Many different therapeutic approaches to DMD have been tested, including cell-based and gene-based approaches, exon skipping, induction of expression of the dystrophin paralogue, utrophin, and, most recently the application of the CASPR/Cas9 genome editing system. However, corticosteroid treatment remains the gold standard therapy, even if corticosteroids have shown multiple undesirable side effects. Sertoli cells (SeC) have long been known for their ability to produce immunomodulatory and trophic factors, and have been used in a plethora of experimental models of disease. Recently, microencapsulated porcine SeC (MC-SeC) injected intraperitoneally in dystrophic mice produced morphological and functional benefits in muscles thanks to their release into the circulation of anti-inflammatory factors and heregulin β1, a known inducer of utrophin expression, thus opening a new avenue in the treatment of DMD. In order to stress the potentiality of the use of MC-SeC in the treatment of DMD, here, we examine the principal therapeutic approaches to DMD, and the properties of SeC (either nude or encapsulated into alginate-based microcapsules) and their preclinical and clinical use. Finally, we discuss the potential and future development of this latter approach.Keywords: Duchenne muscular dystrophy; therapeutic approaches; Sertoli cell; muscle inflammation; myopathies; encapsulation; biomaterials Duchenne Muscular Dystrophy (DMD)Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy. Muscular dystrophies are a group of inherited muscle diseases characterized by mutations in specific genes and resulting in muscle degeneration, impaired locomotion and premature death [1,2]. DMD is an X-linked recessive pathology caused by mutations in the dystrophin gene (DMD) usually resulting in the complete absence of this protein. Dystrophin is an essential component of the dystrophin-associated protein complex (DAPC) at the sarcolemma, a complex that ensures the structural and functional integrity of the myofibers during contraction representing a mechanical link between the intracellular cytoskeleton and the extracellular matrix. Absence of dystrophin or other components of the DAPC compromises the integrity of the DAPC itself leading to a susceptibility of myofibers to degeneration

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“…In parallel, novel "dissociative steroids" aim to a broader therapeutic window by separating pharmacodynamic mechanisms responsible for efficacy and side effects. 28,29 Before randomized trial results and innovative treatments become available, natural history studies can provide useful information regarding different GC regimens in DMD.…”

mentioning

confidence: 99%

Prednisone/prednisolone and deflazacort regimens in the CINRG Duchenne Natural History Study

Bello¹,

Gordish‐Dressman²,

Morgenroth³

et al. 2015

Neurology

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164

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Objective: We aimed to perform an observational study of age at loss of independent ambulation (LoA) and side-effect profiles associated with different glucocorticoid corticosteroid (GC) regimens in Duchenne muscular dystrophy (DMD). Methods:We studied 340 participants in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS). LoA was defined as continuous wheelchair use. Effects of prednisone or prednisolone (PRED)/deflazacort (DFZ), administration frequency, and dose were analyzed by time-varying Cox regression. Side-effect frequencies were compared using x 2 test.Results: Participants treated $1 year while ambulatory (n 5 252/340) showed a 3-year median delay in LoA (p , 0.001). Fourteen different regimens were observed. Nondaily treatment was common for PRED (37%) and rare for DFZ (3%). DFZ was associated with later LoA than PRED (hazard ratio 0.294 6 0.053 vs 0.490 6 0.08, p 5 0.003; 2-year difference in median LoA with daily administration, p , 0.001). Average dose was lower for daily PRED (0.56 mg/kg/d, 75% of recommended) than daily DFZ (0.75 mg/kg/d, 83% of recommended, p , 0.001). DFZ showed higher frequencies of growth delay (p , 0.001), cushingoid appearance (p 5 0.002), and cataracts (p , 0.001), but not weight gain.Conclusions: Use of DFZ was associated with later LoA and increased frequency of side effects.Differences in standards of care and dosing complicate interpretation of this finding, but stratification by PRED/DFZ might be considered in clinical trials. This study emphasizes the necessity of a randomized, blinded trial of GC regimens in DMD.

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VBP15, a novel anti‐inflammatory and membrane‐stabilizer, improves muscular dystrophy without side effects

Cited by 156 publications

References 81 publications

Sulforaphane Attenuates Muscle Inflammation in Dystrophin-deficient mdx Mice via NF-E2-related Factor 2 (Nrf2)-mediated Inhibition of NF-κB Signaling Pathway

Sulforaphane Attenuates Muscle Inflammation in Dystrophin-deficient mdx Mice via NF-E2-related Factor 2 (Nrf2)-mediated Inhibition of NF-κB Signaling Pathway

Employment of Microencapsulated Sertoli Cells as a New Tool to Treat Duchenne Muscular Dystrophy

Prednisone/prednisolone and deflazacort regimens in the CINRG Duchenne Natural History Study

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