Abstract
Duchenne muscular dystrophy (DMD) is the most common and cureless muscle pediatric genetic disease, which is caused by the lack or the drastically reduced expression of dystrophin. Experimental therapeutic approaches for DMD have been mainly focused in recent years on attempts to restore the expression of dystrophin. While significant progress was achieved, the therapeutic benefit of treated patients is still unsatisfactory. Efficiency in gene therapy for DMD is hampered not only by incompletely resolved technical issues, but likely also due to the progressive nature of DMD. It is indeed suspected that some of the secondary pathologies, which are evolving over time in DMD patients, are not fully corrected by the restoration of dystrophin expression. We recently identified perturbations of the mevalonate pathway and of cholesterol metabolism in DMD patients. Taking advantage of the mdx model for DMD, we then demonstrated that some of these perturbations are improved by treatment with the cholesterol-lowering drug, simvastatin. In the present investigation, we tested whether the combination of the restoration of dystrophin expression with simvastatin treatment could have an additive beneficial effect in the mdx model. We confirmed the positive effects of microdystrophin, and of simvastatin, when administrated separately, but detected no additive effect by their combination. Thus, the present study does not support an additive beneficial effect by combining dystrophin restoration with a metabolic normalization by simvastatin.
Highlights
Duchenne muscular dystrophy (DMD) is the most common inherited pediatric muscle disorder
The comparison groups included: (1) control healthy C57Bl/6 (WT), (2) untreated mdx, (3) mdx treated with Simvastatin only, (4) mdx treated with AAV-microdystrophin at low titer, (5) mdx treated with AAV-microdystrophin at low titer plus simvastatin, and (6) mdx treated with AAV-microdystrophin at high titer (Figure 1a)
Expression of the microdystrophin (μ-dys) in the the same (TA) muscles was quantified by RT-quantitative real-time polymerase chain reaction (qPCR). (d) The expression of the microdystrophin in the TA muscles was quantified by a Western blotting (n = 6)
Summary
Duchenne muscular dystrophy (DMD) is the most common inherited pediatric muscle disorder. It is an X-linked genetic progressive myopathy characterized by muscle wasting and weakness, which leads to loss of motor functions, cardiac and respiratory impairment, and premature death [1]. DMD occurs at a rate of approximately 1:5000 male births and arises due to mutations in the dystrophin gene. The disease is caused by a deficiency of functional dystrophin, a critical component of the dystrophin-associated protein complex that links the cytoskeleton with the extracellular matrix in skeletal and cardiac muscles [2]. The primary direct consequence of the disruption of this linkage by the lack of dystrophin is thought to involve sarcolemma destabilization, perturbation of Ca2 + homeostasis, activation of proteases, mitochondrial damage and tissue degeneration. The only routinely used medication for DMD patients is glucosteroid drugs, which can at best only slightly delay the disease progression [3], gene correction and gene replacement technologies have emerged in recent years as promising treatment options for DMD
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