Standard of care versus new-wave corticosteroids in the treatment of Duchenne muscular dystrophy: Can we do better?

Kourakis, Stephanie; Timpani, Cara A; Campelj, Dean G; Hafner, Patricia; Gueven, Nuri; Fischer, Dirk; Rybalka, Emma

doi:10.1186/s13023-021-01758-9

Cited by 58 publications

(56 citation statements)

References 129 publications

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“…However, because improved clinical outcomes in DMD patients were observed in patients with preserved LVEF only, the evidence of corticosteroid treatment in DMD patients with reduced LVEF is insufficient. Moreover, the beneficial association of corticosteroid treatment in late‐stage DMD patients had few evidence 18,24 . Nevertheless, the lower rate use of corticosteroids in the present study is one of the limitations.…”

Section: Discussionmentioning

confidence: 67%

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The association between cardiac involvement and long‐term clinical outcomes in patients with Duchenne muscular dystrophy

Cha

Kim

et al. 2022

ESC Heart Failure

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Aims Despite advances in contemporary cardiopulmonary therapies, cardiomyopathy remains the leading cause of death in patients with Duchenne muscular dystrophy (DMD). Also, the long-term clinical outcomes of patients with DMD and cardiomyopathy is unknown. This study investigated long-term clinical outcomes and their associated factors in patients with late-stage DMD. Methods and results A total of 116 patients with late-stage DMD (age > 15 years) were enrolled in this retrospective study. All enrolled patients were followed up at a single tertiary referral hospital. LV systolic dysfunction was dichotomously defined as reduced [left ventricular ejection fraction (LVEF) ≤ 40%] vs. preserved [>40%] based on the initial echocardiographic result. The primary endpoint was all-cause death. The secondary endpoint was a composite event defined as death or unexpected hospitalization due to cardiovascular reasons including chest pain, dyspnoea, and generalized oedema. The patients were divided into preserved (n = 84, 72.4%) and reduced LVEF groups (n = 32, 27.6%). The mean age was 20.8 ± 5.9 years, the mean disease duration, 8.8 ± 3.7 years, and the mean follow-up duration, 1708 ± 659 days. For primary endpoint, the reduced LVEF group showed a lower rate of overall survival (Reduced LVEF vs. Preserved LVEF; 81.3% vs. 98.8%, log-rank P = 0.005). In the multivariable Cox regression analysis, brain-natriuretic peptide (BNP) level (adjusted hazard ratio [HR] 1.088, 95% confidence interval [CI] 1.019-1.162, P = 0.011) and diuretic use (adjusted HR 9.279, 95%CI 1.651-52.148, P = 0.011) were significant predictors of all-cause death in patients with DMD. For the secondary endpoint, the reduced LVEF group had a lower rate of freedom from composite events than the preserved LVEF group (65.6% vs. 86.9%, log-rank P = 0.005). In the multivariable Cox regression analysis, BNP level (adjusted HR 1.057, 95%CI 1.005-1.112, P = 0.032) and diuretic use (adjusted HR 4.189, 95% CI 1.704-10.296, P = 0.002) were significant predictors of the composite event in patients with DMD. Conclusions Patients with DMD and reduced LVEF had worse clinical outcomes than those with preserved LVEF. BNP level and diuretic use were associated with adverse clinical outcomes in patients with late-stage DMD, irrespective of LVEF.

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Section: Discussionmentioning

confidence: 67%

“…The current guidelines recommend corticosteroids, ACEi, mineralocorticoid receptor antagonists, and beta‐blockers for reducing cardiovascular events in patients with DMD 5,24 . Gernot et al .…”

Section: Discussionmentioning

confidence: 99%

The association between cardiac involvement and long‐term clinical outcomes in patients with Duchenne muscular dystrophy

Cha

Kim

et al. 2022

ESC Heart Failure

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“…In dystrophin-deficient myofibers, the primary structural defect brings to a progressive muscle degeneration and aberrant signaling during contraction [ 3 ], as well as weakness, muscle loss, oxidative stress, and inflammation [ 2 , 5 ]. To date, no resolutive cure is available for DMD and the most effective treatment regimen aimed to relieve symptoms and slow disease progression entails the use of anti-inflammatory glucocorticoids [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

β-Dystroglycan Restoration and Pathology Progression in the Dystrophic mdx Mouse: Outcome and Implication of a Clinically Oriented Study with a Novel Oral Dasatinib Formulation

et al. 2021

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ROS-activated cSrc tyrosine kinase (TK) promotes the degradation of β-dystroglycan (β-DG), a dystrophin-glycoprotein complex component, which may reinforce damaging signals in Duchenne muscular dystrophy (DMD). Therefore, cSrc-TK represents a promising therapeutic target. In mdx mice, a 4-week subcutaneous treatment with dasatinib (DAS), a pan-Src-TKs inhibitor approved as anti-leukemic agent, increased muscle β-DG, with minimal amelioration of morphofunctional indices. To address possible dose/pharmacokinetic (PK) issues, a new oral DAS/hydroxypropyl(HP)-β-cyclodextrin(CD) complex was developed and chronically administered to mdx mice. The aim was to better assess the role of β-DG in pathology progression, meanwhile confirming DAS mechanism of action over the long-term, along with its efficacy and tolerability. The 4-week old mdx mice underwent a 12-week treatment with DAS/HP-β-CD10% dissolved in drinking water, at 10 or 20 mg/kg/day. The outcome was evaluated via in vivo/ex vivo disease-relevant readouts. Oral DAS/HP-β-CD efficiently distributed in mdx mice plasma and tissues in a dose-related fashion. The new DAS formulation confirmed its main upstream mechanism of action, by reducing β-DG phosphorylation and restoring its levels dose-dependently in both diaphragm and gastrocnemius muscle. However, it modestly improved in vivo neuromuscular function, ex vivo muscle force, and histopathology, although the partial recovery of muscle elasticity and the decrease of CK and LDH plasma levels suggest an increased sarcolemmal stability of dystrophic muscles. Our clinically oriented study supports the interest in this new, pediatric-suitable DAS formulation for proper exposure and safety and for enhancing β-DG expression. This latter mechanism is, however, not sufficient by itself to impact on pathology progression. In-depth analyses will be dedicated to elucidating the mechanism limiting DAS effectiveness in dystrophic settings, meanwhile assessing its potential synergy with dystrophin-based molecular therapies.

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“…Though a few mutation-specific compounds are used in clinical settings and other cell and gene therapy-based approaches are under extensive investigation, drugs that act mostly as anti-inflammatory agents, such as glucocorticoids (GCs), still serve as the gold standard of care for all patients suffering from DMD 14 . Apart from their indisputable beneficial effects in prolonging ambulation and improving the quality of the patient’s life, they, unfortunately, entail a list of multi-organ side effects 15 . This emphasizes the persistent need to evaluate novel targets to ameliorate disease symptoms, which could also potentially be applicable in the emerging concept of combined therapies for DMD patients 16 .…”

Section: Introductionmentioning

confidence: 99%

miR-378 affects metabolic disturbances in the mdx model of Duchenne muscular dystrophy

Podkalicka

Mucha

Kaziród

et al. 2022

Sci Rep

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Although Duchenne muscular dystrophy (DMD) primarily affects muscle tissues, the alterations to systemic metabolism manifested in DMD patients contribute to the severe phenotype of this fatal disorder. We propose that microRNA-378a (miR-378) alters carbohydrate and lipid metabolism in dystrophic mdx mice. In our study, we utilized double knockout animals which lacked both dystrophin and miR-378 (mdx/miR-378−/−). RNA sequencing of the liver identified 561 and 194 differentially expressed genes that distinguished mdx versus wild-type (WT) and mdx/miR-378−/− versus mdx counterparts, respectively. Bioinformatics analysis predicted, among others, carbohydrate metabolism disorder in dystrophic mice, as functionally proven by impaired glucose tolerance and insulin sensitivity. The lack of miR-378 in mdx animals mitigated those effects with a faster glucose clearance in a glucose tolerance test (GTT) and normalization of liver glycogen levels. The absence of miR-378 also restored the expression of genes regulating lipid homeostasis, such as Acly, Fasn, Gpam, Pnpla3, and Scd1. In conclusion, we report for the first time that miR-378 loss results in increased systemic metabolism of mdx mice. Together with our previous finding, demonstrating alleviation of the muscle-related symptoms of DMD, we propose that the inhibition of miR-378 may represent a new strategy to attenuate the multifaceted symptoms of DMD.

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Standard of care versus new-wave corticosteroids in the treatment of Duchenne muscular dystrophy: Can we do better?

Cited by 58 publications

References 129 publications

The association between cardiac involvement and long‐term clinical outcomes in patients with Duchenne muscular dystrophy

The association between cardiac involvement and long‐term clinical outcomes in patients with Duchenne muscular dystrophy

β-Dystroglycan Restoration and Pathology Progression in the Dystrophic mdx Mouse: Outcome and Implication of a Clinically Oriented Study with a Novel Oral Dasatinib Formulation

miR-378 affects metabolic disturbances in the mdx model of Duchenne muscular dystrophy

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