Novel compounds for the treatment of Duchenne muscular dystrophy: emerging therapeutic agents.
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ABSTRACT:
SUBMITTER: Wilton SD
PROVIDER: S-EPMC3681176 | biostudies-literature | 2011
REPOSITORIES: biostudies-literature
Publications
Novel compounds for the treatment of Duchenne muscular dystrophy: emerging therapeutic agents.
Wilton Steve D SD Fletcher Sue S
The application of clinical genetics 20110310
The identification of dystrophin and the causative role of mutations in this gene in Duchenne and Becker muscular dystrophies (D/BMD) was expected to lead to timely development of effective therapies. Despite over 20 years of research, corticosteroids remain the only available pharmacological treatment for DMD, although significant benefits and extended life have resulted from advances in the clinical care and management of DMD individuals. Effective treatment of DMD will require dystrophin rest ...[more]
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Project description:Duchenne muscular dystrophy (DMD) is a progressive X-linked degenerative muscle disease due to mutations in the DMD gene. Genetic confirmation has become standard in recent years. Improvements in the standard of care for DMD have led to improved survival. Novel treatments for DMD have focused on reducing the dystrophic mechanism of the muscle disease, modulating utrophin protein expression, and restoring dystrophin protein expression. Among the strategies to reduce the dystrophic mechanisms are 1) inhibiting inflammation, 2) promoting muscle growth and regeneration, 3) reducing fibrosis, and 4) facilitating mitochondrial function. The agents under investigation include a novel steroid, myostatin inhibitors, idebenone, an anti-CTGF antibody, a histone deacetylase inhibitor, and cardiosphere-derived cells. For utrophin modulation, AAV-mediated gene therapy with GALGT2 is currently being investigated to upregulate utrophin expression. Finally, the strategies for dystrophin protein restoration include 1) nonsense readthrough, 2) synthetic antisense oligonucleotides for exon skipping, and 3) AAV-mediated micro/minidystrophin gene delivery. With newer agents, we are witnessing the use of more advanced biotechnological methods. Although these potential breakthroughs provide significant promise, they may also raise new questions regarding treatment effect and safety.
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Project description:Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy in childhood. It is caused by mutations of the DMD gene, leading to progressive muscle weakness, loss of independent ambulation by early teens, and premature death due to cardiorespiratory complications. The diagnosis can usually be made after careful review of the history and examination of affected boys presenting with developmental delay, proximal weakness, and elevated serum creatine kinase, plus confirmation by muscle biopsy or genetic testing. Precise characterization of the DMD mutation is important for genetic counseling and individualized treatment. Current standard of care includes the use of corticosteroids to prolong ambulation and to delay the onset of secondary complications. Early use of cardioprotective agents, noninvasive positive pressure ventilation, and other supportive strategies has improved the life expectancy and health-related quality of life for many young adults with DMD. New emerging treatment includes viral-mediated microdystrophin gene replacement, exon skipping to restore the reading frame, and nonsense suppression therapy to allow translation and production of a modified dystrophin protein. Other potential therapeutic targets involve upregulation of compensatory proteins, reduction of the inflammatory cascade, and enhancement of muscle regeneration. So far, data from DMD clinical trials have shown limited success in delaying disease progression; unforeseen obstacles included immune response against the generated mini-dystrophin, inconsistent evidence of dystrophin production in muscle biopsies, and failure to demonstrate a significant improvement in the primary outcome measure, as defined by the 6-minute walk test in some studies. The long-term safety and efficacy of emerging treatments will depend on the selection of appropriate clinical end points and sensitive biomarkers to detect meaningful changes in disease progression. Correction of the underlying mutations using new gene-editing technologies and corticosteroid analogs with better safety profiles offers renewed hope for many individuals with DMD and their families.
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Project description:Duchenne muscular dystrophy (DMD) is the most common, severe childhood form of muscular dystrophy. Treatment is limited to glucocorticoids that have the benefit of prolonging ambulation by approximately 2 years and preventing scoliosis. Finding a more satisfactory treatment should focus on maintaining long-term efficacy with a minimal side effect profile.Authors discuss different therapeutic strategies that have been used in pre-clinical and clinical settings.Multiple treatment approaches have emerged. Most attractive are molecular-based therapies that can express the missing dystrophin protein (exon skipping or mutation suppression) or a surrogate gene product (utrophin). Other approaches include increasing the strength of muscles (myostatin inhibitors), reducing muscle fibrosis and decreasing oxidative stress. Additional targets include inhibiting NF-?B to reduce inflammation or promoting skeletal muscle blood flow and muscle contractility using phosphodiesterase inhibitors or nitric oxide (NO) donors. The potential for each of these treatment strategies to enter clinical trials is a central theme of discussion. The review emphasizes that the goal of treatment should be to find a product at least as good as glucocorticoids with a lower side effect profile or with a significant glucocorticoid sparing effect.
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Project description:Duchenne muscular dystrophy (DMD) is the most common childhood muscular dystrophy affecting ~1:5000 live male births. Following the identification of pathogenic variations in the dystrophin gene in 1986, the underlining genotype/phenotype correlations emerged and the role of the dystrophin protein was elucidated in skeletal, smooth, and cardiac muscles, as well as in the brain. When the dystrophin protein is absent or quantitatively or qualitatively modified, the muscle cannot sustain the stress of repeated contractions. Dystrophin acts as a bridging and anchoring protein between the sarcomere and the sarcolemma, and its absence or reduction leads to severe muscle damage that eventually cannot be repaired, with its ultimate substitution by connective tissue and fat. The advances of an understanding of the molecular pathways affected in DMD have led to the development of many therapeutic strategies that tackle different aspects of disease etiopathogenesis, which have recently led to the first successful approved orphan drugs for this condition. The therapeutic advances in this field have progressed exponentially, with second-generation drugs now entering in clinical trials as gene therapy, potentially providing a further effective approach to the condition.
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Project description:Neuromuscular disorders encompass a heterogeneous group of conditions that impair the function of muscles, motor neurons, peripheral nerves, and neuromuscular junctions. Being the most common and most severe type of muscular dystrophy, Duchenne muscular dystrophy (DMD), is caused by mutations in the X-linked dystrophin gene. Loss of dystrophin protein leads to recurrent myofiber damage, chronic inflammation, progressive fibrosis, and dysfunction of muscle stem cells. Over the last few years, there has been considerable development of diagnosis and therapeutics for DMD, but current treatments do not cure the disease. Here, we review the current status of DMD pathogenesis and therapy, focusing on mutational spectrum, diagnosis tools, clinical trials, and therapeutic approaches including dystrophin restoration, gene therapy, and myogenic cell transplantation. Furthermore, we present the clinical potential of advanced strategies combining gene editing, cell-based therapy with tissue engineering for the treatment of muscular dystrophy.
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Project description:BackgroundAdiponectin (ApN) is a hormone known to exhibit insulin-sensitizing, fat-burning, and anti-inflammatory properties in several tissues, including the skeletal muscle. Duchenne muscular dystrophy (DMD) is a devastating disease characterized by dystrophin deficiency with subsequent chronic inflammation, myofiber necrosis, and impaired regeneration. Previously, we showed that transgenic up-regulation of ApN could significantly attenuate the dystrophic phenotype in mdx mice (model of DMD). Recently, an orally active ApN receptor agonist, AdipoRon, has been identified. This synthetic small molecule has the advantage of being more easily produced and administrable than ApN. The aim of this study was to investigate the potential effects of AdipoRon on the dystrophic muscle.MethodsFour-week-old mdx mice (n = 6-9 per group) were orally treated with AdipoRon (mdx-AR) for 8 weeks and compared with untreated (mdx) mice and to control (wild-type) mice. In vivo functional tests were carried out to measure the global force and endurance of mice. Ex vivo biochemical and molecular analyses were performed to evaluate the pathophysiology of the skeletal muscle. Finally, in vitro tests were conducted on primary cultures of healthy and DMD human myotubes.ResultsAdipoRon treatment mitigated oxidative stress (-30% to 45% for 4-hydroxy-2-nonenal and peroxiredoxin 3, P < 0.0001) as well as inflammation in muscles of mdx mice (-35% to 65% for interleukin 1 beta, tumour necrosis factor alpha, and cluster of differentiation 68, a macrophage maker, P < 0.0001) while increasing the anti-inflammatory cytokine, interleukin 10 (~5-fold, P < 0.0001). AdipoRon also improved the myogenic programme as assessed by a ~2-fold rise in markers of muscle proliferation and differentiation (P < 0.01 or less vs. untreated mdx). Plasma lactate dehydrogenase and creatine kinase were reduced by 30-40% in mdx-AR mice, reflecting less sarcolemmal damage (P < 0.0001). When compared with untreated mdx mice, mdx-AR mice exhibited enhanced physical performance with an increase in both muscle force and endurance and a striking restoration of the running capacity during eccentric exercise. AdipoRon mainly acted through ApN receptor 1 by increasing AMP-activated protein kinase signalling, which led to repression of nuclear factor-kappa B, up-regulation of utrophin (a dystrophin analogue), and a switch towards an oxidative and more resistant fibre phenotype. The effects of AdipoRon were then recapitulated in human DMD myotubes.ConclusionsThese results demonstrate that AdipoRon exerts several beneficial effects on the dystrophic muscle. This molecule could offer promising therapeutic prospect for managing DMD or other muscle and inflammatory disorders.
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2024-03-07 | PXD038406 | Pride
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