Abstract
BackgroundIn the search of genetic determinants of Duchenne muscular dystrophy (DMD) severity, LTBP4, a member of the latent TGF-β binding protein family, emerged as an important predictor of functional outcome trajectories in mice and humans. Nonsynonymous single-nucleotide polymorphisms in LTBP4 gene associate with prolonged ambulation in DMD patients, whereas an in-frame insertion polymorphism in the mouse LTBP4 locus modulates disease severity in mice by altering proteolytic stability of the Ltbp4 protein and release of transforming growth factor-β (TGF-β). Givinostat, a pan-histone deacetylase inhibitor currently in phase III clinical trials for DMD treatment, significantly reduces fibrosis in muscle tissue and promotes the increase of the cross-sectional area (CSA) of muscles in mdx mice. In this study, we investigated the activity of Givinostat in mdx and in D2.B10 mice, two mouse models expressing different Ltbp4 variants and developing mild or more severe disease as a function of Ltbp4 polymorphism.MethodsGivinostat and steroids were administrated for 15 weeks in both DMD murine models and their efficacy was evaluated by grip strength and run to exhaustion functional tests. Histological examinations of skeletal muscles were also performed to assess the percentage of fibrotic area and CSA increase.ResultsGivinostat treatment increased maximal normalized strength to levels that were comparable to those of healthy mice in both DMD models. The effect of Givinostat in both grip strength and exhaustion tests was dose-dependent in both strains, and in D2.B10 mice, Givinostat outperformed steroids at its highest dose. The in vivo treatment with Givinostat was effective in improving muscle morphology in both mdx and D2.B10 mice by reducing fibrosis.ConclusionOur study provides evidence that Givinostat has a significant effect in ameliorating both muscle function and histological parameters in mdx and D2.B10 murine models suggesting a potential benefit also for patients with a poor prognosis LTBP4 genotype.
Highlights
In the search of genetic determinants of Duchenne muscular dystrophy (DMD) severity, LTBP4, a member of the latent transforming growth factor-β (TGF-β) binding protein family, emerged as an important predictor of functional outcome trajectories in mice and humans
Our study provides evidence that Givinostat has a significant effect in ameliorating both muscle function and histological parameters in mdx and D2.B10 murine models suggesting a potential benefit for patients with a poor prognosis LTBP4 genotype
To date there is no standard therapy for DMD patients that leads to the healing of the disease; glucocorticoid (GC) steroid treatment, corrective orthopedic surgery, and assisted ventilation can contribute to improve the quality of life of patients and to delay disease progression [3]
Summary
In the search of genetic determinants of Duchenne muscular dystrophy (DMD) severity, LTBP4, a member of the latent TGF-β binding protein family, emerged as an important predictor of functional outcome trajectories in mice and humans. Nonsynonymous single-nucleotide polymorphisms in LTBP4 gene associate with prolonged ambulation in DMD patients, whereas an in-frame insertion polymorphism in the mouse LTBP4 locus modulates disease severity in mice by altering proteolytic stability of the Ltbp protein and release of transforming growth factor-β (TGF-β). Givinostat, a pan-histone deacetylase inhibitor currently in phase III clinical trials for DMD treatment, significantly reduces fibrosis in muscle tissue and promotes the increase of the cross-sectional area (CSA) of muscles in mdx mice. GC steroid treatment (mainly prednisone and Deflazacort) was shown to beneficially influence all disease trajectories, including survival and prolonged ambulation in DMD patients [9,10,11], but this benefit comes at the cost of significant side effects such as body weight (BW) increase, growth stunting, Cushing-like symptoms, mood changes, increased incidence of fractures, and susceptibility to infections [12, 13]. There is a clear need for a broadly active and well-tolerated treatment for DMD patients
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