Human Molecular Genetics Advance Access originally published online on July 31, 2009
Human Molecular Genetics 2009 18(21):4089-4101; doi:10.1093/hmg/ddp358
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Evaluation of the therapeutic potential of carbonic anhydrase inhibitors in two animal models of dystrophin deficient muscular dystrophy
1 Centre de Génétique Moléculaire et Cellulaire, UMR 5534, Université Lyon 1, 69622 Villeurbanne Cedex, France 2 Laboratory of Molecular Myology, Department of Neurology, Friedrich Baur Institute, Ludwig Maximilians University of Munich, Munich, Germany 3 Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada, V5A 1S6 4 Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK
* To whom correspondence should be addressed at: CNRS-CGMC-UMR5534, Universite Lyon-1 Claude Bernard, Batiment Mendel, 43 bld du 11 Novembre, 69622 Villeurbanne Cedex, France. Tel: +33 472432951; Fax: +33 472432951; Email: segalat{at}cgmc.univ-lyon1.fr
Received June 8, 2009; Revised July 6, 2009; Accepted July 27, 2009
Duchenne Muscular Dystrophy is an inherited muscle degeneration disease for which there is still no efficient treatment. However, compounds active on the disease may already exist among approved drugs but are difficult to identify in the absence of cellular models. We used the Caenorhabditis elegans animal model to screen a collection of 1000 already approved compounds. Two of the most active hits obtained were methazolamide and dichlorphenamide, carbonic anhydrase inhibitors widely used in human therapy. In C. elegans, these drugs were shown to interact with CAH-4, a putative carbonic anhydrase. The therapeutic efficacy of these compounds was further validated in long-term experiments on mdx mice, the mouse model of Duchenne Muscular Dystrophy. Mice were treated for 120 days with food containing methazolamide or dichlorphenamide at two doses each. Musculus tibialis anterior and diaphragm muscles were histologically analyzed and isometric muscle force was measured in M. extensor digitorum longus. Both substances increased the tetanic muscle force in the treated M. extensor digitorum longus muscle group, dichlorphenamide increased the force significantly by 30%, but both drugs failed to increase resistance of muscle fibres to eccentric contractions. Histological analysis revealed a reduction of centrally nucleated fibers in M. tibialis anterior and diaphragm in the treated groups. These studies further demonstrated that a C. elegans-based screen coupled with a mouse model validation strategy can lead to the identification of potential pharmacological agents for rare diseases.
G.J. and C.P. contributed equally to the study.