Gentamicin treatment in exercised mdx mice: Identification of dystrophin-sensitive pathways and evaluation of efficacy in work-loaded dystrophic muscle

A, De Luca; Nico, Beatrice; Rolland, Jean-François; Cozzoli, Anna; Burdi, Rosa; Mangieri, Domenica; Giannuzzi, Viviana; Liantonio, Antonella; Cippone, Valentina; Bellis, Michela De; Nicchia, Grazia Paola; Camerino, Giulia Maria; Frigeri, Antonio; Svelto, María; Camerino, Diana Conte

doi:10.1016/j.nbd.2008.07.009

Cited by 43 publications

(53 citation statements)

References 51 publications

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“…Approximately 5%–15% of DMD cases are caused by nonsense mutation in the dystrophin gene. A way to efficiently rescue dystrophin expression uses aminoglycoside antibiotics like gentamycin, which interfere with the ribosome ability to recognize premature-termination codons (PTC) and thus restore open reading frame [192, 193]. This however results in long-term toxicity with few good-responder patients [194].…”

Section: Therapies For Dmd: From Muscle To Brainmentioning

confidence: 99%

Dystrophins, Utrophins, and Associated Scaffolding Complexes: Role in Mammalian Brain and Implications for Therapeutic Strategies

Perronnet

Vaillend

2010

Journal of Biomedicine and Biotechnology

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Two decades of molecular, cellular, and functional studies considerably increased our understanding of dystrophins function and unveiled the complex etiology of the cognitive deficits in Duchenne muscular dystrophy (DMD), which involves altered expression of several dystrophin-gene products in brain. Dystrophins are normally part of critical cytoskeleton-associated membrane-bound molecular scaffolds involved in the clustering of receptors, ion channels, and signaling proteins that contribute to synapse physiology and blood-brain barrier function. The utrophin gene also drives brain expression of several paralogs proteins, which cellular expression and biological roles remain to be elucidated. Here we review the structural and functional properties of dystrophins and utrophins in brain, the consequences of dystrophins loss-of-function as revealed by numerous studies in mouse models of DMD, and we discuss future challenges and putative therapeutic strategies that may compensate for the cognitive impairment in DMD based on experimental manipulation of dystrophins and/or utrophins brain expression.

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Section: Therapies For Dmd: From Muscle To Brainmentioning

confidence: 99%

Dystrophins, Utrophins, and Associated Scaffolding Complexes: Role in Mammalian Brain and Implications for Therapeutic Strategies

Perronnet

Vaillend

2010

Journal of Biomedicine and Biotechnology

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“…In a 6-month trial of CAT-1041 on individually housed mdx mice with ad libitum access to a voluntary running wheel, a model used to exacerbate the relatively mild dystrophic phenotype of mdx mice (18,19), the CAT-1041 treatment group consistently ran greater distances than the untreated mice ( Figure 4A Immunoblotting of quadriceps revealed that CAT-1041 reduced the expression of the NF-κB components p65, p105, p50, RelB, and p100, while p52 expression trended towards a reduction and the RelB/p65 ratio trended towards an increase ( Figure 5E). In agreement with a decrease of the NF-κB system, lower levels of the inflammatory markers osteopontin, IL-6, IL-4, and MMP2, as well as the fibrosis markers FSP-1 and fibronectin were found ( Figure 5F).…”

Section: Resultsmentioning

confidence: 99%

Disease-modifying effects of orally bioavailable NF-κB inhibitors in dystrophin-deficient muscle

Hammers¹,

Sleeper

Forbes

et al. 2016

JCI Insight

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“…These data show a high correlation between the benefits in mdx mice and humans with respect to dystrophin replacement indicating that a drug-induced improvement in dystrophin levels will have a high translational benefit. Indeed, equivalence in translational benefit is demonstrated by similar results with gentamicin upregulation of dystrophin in dystrophic mice [36] and humans [37]. This tight correlation may not be the case for other interventions that modify complex events downstream of the dystrophin deficiency, e.g.…”

Section: Early Phase Versus Later Phase Experimentsmentioning

confidence: 99%

Enhancing translation: Guidelines for standard pre-clinical experiments in mdx mice

Willmann

Benatar

et al. 2012

Neuromuscular Disorders

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Duchenne Muscular Dystrophy is an X-linked disorder that affects boys and leads to muscle wasting and death due to cardiac involvement and respiratory complications. The cause is the absence of dystrophin, a large structural protein indispensable for muscle cell function and viability. Neither an effective treatment nor a cure is available at the present time. The mdx mouse has become the standard animal model for pre-clinical evaluation of potential therapeutic treatments. Recent years have seen a rapid increase in the number of experimental compounds being evaluated in the mdx mouse. There is, however, much variability in the design of these pre-clinical experimental studies. This has made it difficult to interpret and compare published data from different laboratories and to evaluate the potential of a treatment for application to patients. The authors therefore propose the introduction of a standard study design for the mdx mouse model. Several aspects, including animal care, sampling times and choice of tissues, as well as recommended endpoints and methodologies are addressed and, for each aspect, a standard procedure is proposed. Testing of all new molecules/drugs using a widely accepted and agreed upon standard experimental protocol would greatly improve the power of pre-clinical experimentations and help identifying promising therapies for the translation into clinical trials for boys with Duchenne Muscular Dystrophy.

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Gentamicin treatment in exercised mdx mice: Identification of dystrophin-sensitive pathways and evaluation of efficacy in work-loaded dystrophic muscle

Cited by 43 publications

References 51 publications

Dystrophins, Utrophins, and Associated Scaffolding Complexes: Role in Mammalian Brain and Implications for Therapeutic Strategies

Dystrophins, Utrophins, and Associated Scaffolding Complexes: Role in Mammalian Brain and Implications for Therapeutic Strategies

Disease-modifying effects of orally bioavailable NF-κB inhibitors in dystrophin-deficient muscle

Enhancing translation: Guidelines for standard pre-clinical experiments in mdx mice

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