Long-term blinded placebo-controlled study of SNT-MC17/idebenone in the dystrophin deficient mdx mouse: cardiac protection and improved exercise performance

Buyse, Gunnar; Mieren, Gerry Van der; Erb, Michael; D'hooge, Jan; Herijgers, Paul; Verbeken, Erik; Jara, Alejandro; Bergh, An Van Den; Mertens, Luc; Courdier-Früh, Isabelle; Barzaghi, Patrizia; Meier, Thomas

doi:10.1093/eurheartj/ehn406

Cited by 89 publications

(62 citation statements)

References 24 publications

(21 reference statements)

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“…We observed no systolic dysfunction in 12-mo-old mdx mice, which is consistent with findings from Jearawiriyapaisarn et al (12). Previous reports suggest that systolic dysfunction may develop with age (15)(16)(17)(18). The reasons for these discrepancies are not known, but may be related to differences in the mdx strains used or perhaps other differences in genetic backgrounds.…”

Section: Discussionsupporting

confidence: 90%

“…The same study also reported a reduction in several possible early markers of cardiomyopathy seen before the onset of cardiac dysfunction (8). It is well established that older mdx mice show an increase in cardiac mass and diastolic dysfunction (12,(15)(16)(17), providing us an excellent model to examine the effects of sildenafil on established cardiomyopathy. In fact, one study has reported the development of cardiac hypertrophy in mdx mice as early as 16 to 21 wks (12), suggesting that the reduced wall thickness we see in the chronically sildenafil-treated 12-mo-old mdx mice may be indicative of a long-term, sustained improvement.…”

Section: Discussionmentioning

confidence: 74%

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Sildenafil reverses cardiac dysfunction in the mdx mouse model of Duchenne muscular dystrophy

Adamo¹,

Dai²,

Percival

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

146

140

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Duchenne muscular dystrophy (DMD) is a progressive and fatal genetic disorder of muscle degeneration. Patients with DMD lack expression of the protein dystrophin as a result of mutations in the X-linked dystrophin gene. The loss of dystrophin leads to severe skeletal muscle pathologies as well as cardiomyopathy, which manifests as congestive heart failure and arrhythmias. Like humans, dystrophin-deficient mice (mdx mice) show cardiac dysfunction as evidenced by a decrease in diastolic function followed by systolic dysfunction later in life. We have investigated whether sildenafil citrate (Viagra), a phosphodiesterase 5 (PDE5) inhibitor, can be used to ameliorate the age-related cardiac dysfunction present in the mdx mice. By using echocardiography, we show that chronic sildenafil treatment reduces functional deficits in the cardiac performance of aged mdx mice, with no effect on normal cardiac function in WT controls. More importantly, when sildenafil treatment was started after cardiomyopathy had developed, the established symptoms were rapidly reversed within a few days. It is recognized that PDE5 inhibitors can have cardioprotective effects in other models of cardiac damage, but the present study reports a prevention and reversal of pathological cardiac dysfunction as measured by functional analysis in a mouse model of DMD. Overall, the data suggest that PDE5 inhibitors may be a useful treatment for the cardiomyopathy affecting patients with DMD at early and late stages of the disease.cGMP | phosphodiesterase | Viagra | echocardiography

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 74%

Sildenafil reverses cardiac dysfunction in the mdx mouse model of Duchenne muscular dystrophy

Adamo¹,

Dai²,

Percival

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

146

140

View full text Add to dashboard Cite

show abstract

“…In fact, NF-κB activation is induced by several inflammatory mediators, such as IL-1β, TNFα, and metalloproteinases, all molecules found elevated in DMD [57,[98][99][100][101][102]. Active NF-κB is able to translocate to the nucleus, inducing the expression of genes encoding for cytokines and chemokines, cell adhesion molecules, and matrix metalloproteinases [103][104][105][106][107].…”

Section: Crosstalk Between Oxidative Stress and Inflammatory Responsementioning

confidence: 99%

Insights into the Pathogenic Secondary Symptoms Caused by the Primary Loss of Dystrophin

Forcina

Pelosi

Miano

et al. 2017

JFMK

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Duchenne muscular dystrophy (DMD) is an X-linked genetic disease in which the dystrophin gene is mutated, resulting in dysfunctional dystrophin protein. Without dystrophin, the dystrophin-glycoprotein complex (DGC) is unstable, leading to an increase in muscle damage. Moreover, the imbalance between muscle damage and repair leads to a chronic inflammatory response and an increase in the amount of fibrosis over time. The absence of dystrophin at the sarcolemma also delocalizes and downregulates nitric oxide synthase (nNOS) and alters enzymatic antioxidant responses, leading to an increase in oxidative stress. In this review, we analyze the pathogenic role of both inflammation and oxidative stress in muscular dystrophy.

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“…67 Idebenone also ameliorated cardiac diastolic dysfunction and reduced mortality from systolic cardiac pump failure in this model. Considering the generally accepted limitation of the mdx mouse as an animal model for DMD, these potential benefits on skeletal muscle degeneration, endurance, and cardiac function would need to be confirmed in patients with DMD.…”

Section: This Mechanism Thereby Bypasses Complex I-dependent Elementioning

confidence: 72%

Idebenone as a Novel Therapeutic Approach for Duchenne Muscular Dystrophy

Buyse

Gueven

McDonald

2015

European Neurological Review

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Progressive loss of pulmonary function leads to early morbidity and mortality in Duchenne muscular dystrophy (DMD) due to both expiratory impairment with ineffective airway clearance, and inspiratory impairment leading to nocturnal and daytime hypoventilation and respiratory failure. Glucocorticoid steroids have become a mainstay of DMD therapy with well-documented efficacy on muscle strength and respiratory function. However, the side-effect profile restricts their long-term use, particularly in non-ambulant patients. Idebenone improves secondary mitochondrial dysfunction caused by dystrophin deficiency, intracellular calcium accumulation and increased reactive oxygen species (ROS). Idebenone-mediated improved bioenergetics leads to enhanced adenosine triphosphate (ATP) production and reduced ROS. Based on this rationale, idebenone has been investigated clinically for efficacy on reducing respiratory function decline in exploratory phase II (DELPHI) and confirmatory phase III (DELOS) trials. Idebenone significantly reduced the loss of respiratory function in 8-18-year-old DMD patients who were not using concomitant glucocorticoids. These results indicate that idebenone can modify the natural course of respiratory disease progression in DMD, which is relevant in clinical practice where loss of respiratory function continues to be a predominant cause of early morbidity and mortality in DMD. KeywordsDuchenne muscular dystrophy, idebenone, respiratory function, peak expiratory flow, glucocorticoid steroid 1,2 increase quality of life and life expectancy, the disease is still associated with early morbidity and mortality. In DMD, progressive weakness of the chest wall muscles precedes weakness of the diaphragm (used predominantly for inspiratory function) and leads to restrictive lung volume changes measured as reduced total lung capacity and forced vital capacity (FVC). [3][4][5][6][7] Initially, this loss of lung volume results from the inability to pull up the respiratory system to total lung capacity and to push it down to residual volume. In later disease stages, additional restrictions occur as a result of progressing muscle fibrosis and changes in lung and chest wall recoil, thoracic wall compliance and spinal deformities (i.e. scoliosis).In the late first decade the earliest signs of respiratory impairment manifest by reduced static airway pressures (maximal expiratory and inspiratory pressures). The gradual loss of respiratory function in DMD measured by spirometry usually begins early in the second decade and progresses to restrictive pulmonary syndrome, impaired respiratory secretion clearance, life-threatening pulmonary infections due to ineffective cough, nocturnal and daytime hypoventilation, obstructive apnoeas and eventually respiratory failure during the late second or third decade of life. 3,[8][9][10]

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Long-term blinded placebo-controlled study of SNT-MC17/idebenone in the dystrophin deficient mdx mouse: cardiac protection and improved exercise performance

Cited by 89 publications

References 24 publications

Sildenafil reverses cardiac dysfunction in the mdx mouse model of Duchenne muscular dystrophy

Sildenafil reverses cardiac dysfunction in the mdx mouse model of Duchenne muscular dystrophy

Insights into the Pathogenic Secondary Symptoms Caused by the Primary Loss of Dystrophin

Idebenone as a Novel Therapeutic Approach for Duchenne Muscular Dystrophy

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