Potencial terapêutico dos inibidores do proteasoma na distrofia muscular de Duchenne e Becker

Itália - em estudos prévios os autores já tinham demonstrado os benefícios experimentais dos inibidores do proteasoma como o mg-132; nesta pesquisa eles usam a droga bortezomib (velcade) liberada para tratamento do mieloma múltiplo. Em camundongos a droga restaurou a distrofina e melhorou as alterações musculares presentes na doença; utilizado em cultura de células de pacientes com Duchenne e Becker houve aumento da expressão das próteínas da membrana como a distrofina e sarcoglicans. É uma droga potencialmente útil para tratamento da doença e cujo potencial deveria ser explorado em estudos clínicos.

O resumo em inglês da pesquisa pode ser lido abaixo:

(Am. J. Pathol. 2010,176(4):1863-1877)Therapeutic Potential of Proteasome Inhibition in Duchenne and Becker Muscular Dystrophies
Elisabetta Gazzerro, Stefania Assereto, Andrea Bonetto, Federica Sotgia, Sonia Scarfì, Angela Pistorio, Gloria Bonuccelli, Michele Cilli, Claudio Bruno, Federico Zara, Michael P. Lisanti, and Carlo Minetti - Italy

Duchenne muscular dystrophy (DMD) and its milder allelic variant, Becker muscular dystrophy (BMD), result from mutations of the dystrophin gene and lead to progressive muscle deterioration. Enhanced activation of proteasomal degradation underlies critical steps in the pathogenesis of the DMD/BMD dystrophic process. Previously, we demonstrated that treatment with the proteasome inhibitor MG-132 rescues the cell membrane localization of dystrophin and the dystrophin glycoprotein complex in mdx mice, a natural genetic mouse model of DMD. The current work aims to thoroughly define the therapeutic potential in dystrophinopathies of Velcade, a drug that selectively blocks the ubiquitin-proteasome pathway. Velcade is particularly intriguing since it has been approved for the treatment of multiple myeloma. Therefore, its side effects in humans have been explored. Velcade effects were analyzed through two independent methodological approaches. First, we administered the drug systemically in mdx mice over a 2-week period. In this system, Velcade restores the membrane expression of dystrophin and dystrophin glycoprotein complex members and improves the dystrophic phenotype. In a second approach, we treated with the compound explants from muscle biopsies of DMD or BMD patients. We show that the inhibition of the proteasome pathway up-regulates dystrophin, -sarcoglycan, and -dystroglycan protein levels in explants from BMD patients, whereas it increases the proteins of the dystrophin glycoprotein complex in DMD cases.

Fonte: http://distrofiamuscular.net/noticias.htm