Multivariate evaluation of the functional recovery obtained by the overexpression of utrophin in skeletal muscles of the mdx mouse

Gillis, Jean-Marie

doi:10.1016/s0960-8966(02)00088-3

Cited by 26 publications

(20 citation statements)

References 24 publications

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“…Grip force testing and measurement of serum creatine kinase level are also noninvasive. 43 However, identification of an improvement would necessitate the treatment of a maximum number of muscles to see any effect. Another noninvasive procedure pioneered by the group of Straub is magnetic resonance imaging.…”

Section: Discussionmentioning

confidence: 99%

Noninvasive monitoring of therapeutic gene transfer in animal models of muscular dystrophies

et al. 2005

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Muscular dystrophies are a genetically and phenotypically heterogeneous group of degenerative muscle diseases. A subset of them are due to genetic deficiencies in proteins which form the dystrophin-associated complex at the membrane of the myofibers. In this report, we utilized recombinant adeno-associated virus containing a U7 cassette carrying an antisense sequence aimed at inducing exon skipping of the dystrophin gene or containing the a-sarcoglycan gene to alleviate the dystrophic phenotype of the mdx and Sgca-null mice, respectively. As these diseases are characterized by cycle of degeneration/regeneration, we postulated that a reporter gene coadministered at the time of the treatment would make it possible to follow the extent of muscle repair. We observed that the murine secreted alkaline phosphatase (muSeAP) level was very much lower in these animal models than in normal mice. Upon treatment of the dystrophic muscle by gene transfer, the level of muSeAP was restored and correlated with the expression of the therapeutic transgene and with the level of muscle improvement. The system described here provides a simple and noninvasive procedure for monitoring the outcome of a therapeutic strategy involving cell survival.

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Section: Discussionmentioning

confidence: 99%

Noninvasive monitoring of therapeutic gene transfer in animal models of muscular dystrophies

et al. 2005

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“…A higher level of function was achieved, as demonstrated by muscle strength, following the expression of full-length utrophin mRNA in mdx mice (Gillis, 2002). In a different approach, overexprcssion ofutrophin in mdx diaphragm muscle was stimulated by treatment with nitric oxide donors (Chaubourt et al, 2002).…”

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confidence: 99%

Target selection for antisense oligonucleotide induced exon skipping in the dystrophin gene

Errington

Mann

Fletcher

et al. 2003

The Journal of Gene Medicine

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BackgroundDuchenne muscular dystrophy (DMD) is an X‐linked recessive muscle wasting disorder characterised by the absence of the protein dystrophin. Antisense oligonucleotides have been used to re‐direct dystrophin pre‐mRNA processing by blocking sequences crucial to pre‐mRNA splicing, thereby inducing skipping of specific exons. We wished to determine which splicing motifs are most amenable as targets for antisense oligonucleotide induction of efficient and specific skipping of selected exons.MethodsAntisense oligonucleotides were directed at regions of dystrophin exon 19 involved in pre‐mRNA splicing, including the donor and acceptor splice sites and the exon splicing enhancer (ESE). Cultured myotubes were transfected with antisense oligonucleotides at various concentrations and studies undertaken to determine both specificity and efficiency of induced exon 19 skipping.ResultsAntisense oligonucleotides as small as 12 nucleotides targeting the ESE induced consistent and specific skipping of only exon 19 in both human and normal and mdx mouse myotubes. Antisense oligonucleotides directed at the donor and acceptor splice sites also induced specific exon 19 skipping while mismatched antisense oligonucleotides could only induce skipping when delivered at higher concentrations. No other dystrophin exons were removed from the mature mRNA as a consequence of these antisense oligonucleotides treatments.ConclusionsAntisense oligonucleotides directed at the ESE tended to be marginally more efficient than those which targeted the donor or acceptor splice sites, based on their ability to induce specific skipping at lower concentrations. The specificity of exon removal does not appear to be a function of target selection, but may reflect the combination of the splicing motifs and position of that exon in the pre‐mRNA. Copyright © 2003 John Wiley & Sons, Ltd.

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“…We additionally evaluated transgenic mice expressing high levels of utrophin in order to test the sensitivity of our assay ( mdx :utr-tg, Fiona line) 11,12 . The mdx :utr-tg is a robust rescue model of the mdx phenotype with few dystrophic features.…”

Section: Representative Resultsmentioning

confidence: 99%

A Simple and Low-cost Assay for Measuring Ambulation in Mouse Models of Muscular Dystrophy

Gibbs

Crosbie-Watson

2017

JoVE

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Measuring functional outcomes in the treatment of muscular dystrophy is an essential aspect of preclinical testing. The assessment of voluntary ambulation in mouse models is a non-invasive and reproducible activity assay that is directly analogous to measures of patient ambulation such as the six-minute walk test and related mobility scores. Many common methods for testing mouse ambulation speed and distance are based on the open field test, where an animal's free movement within an arena is measured over time. One major downside to this approach is that commercial software and equipment for high-resolution motion tracking is expensive and may require transferring mice to specialized facilities for testing. Here, we describe a low-cost video-based system for measuring mouse ambulation that utilizes free and open-source software. Using this protocol, we demonstrate that voluntary ambulation in the dystrophin-null mdx mouse model for Duchenne muscular dystrophy is decreased relative to wild-type mouse activity. In mdx mice expressing the utrophin transgene, these activity deficits are not observed and the total distance travelled is indistinguishable from wild-type mice. This method is effective for measuring changes in voluntary ambulation associated with dystrophic pathology, and provides a versatile platform that can be readily adapted to diverse research settings.

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Multivariate evaluation of the functional recovery obtained by the overexpression of utrophin in skeletal muscles of the mdx mouse

Cited by 26 publications

References 24 publications

Noninvasive monitoring of therapeutic gene transfer in animal models of muscular dystrophies

Noninvasive monitoring of therapeutic gene transfer in animal models of muscular dystrophies

Target selection for antisense oligonucleotide induced exon skipping in the dystrophin gene

A Simple and Low-cost Assay for Measuring Ambulation in Mouse Models of Muscular Dystrophy

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