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Localized Treatment with a Novel FDA-Approved Proteasome Inhibitor Blocks the Degradation of Dystrophin and Dystrophin-Associated Proteins in mdx Mice
Gloria Bonuccelli, Federica Sotgia, Franco Capozza, Elisabetta Gazzerro, Carlo Minetti and Michael P. Lisanti
volume 6 | issue 10
15 May 2007Pages: 1242 - 1248
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Duchenne Muscular Dystrophy (DMD) is an incurable inherited disease of childhood, characterized by progressive muscle degeneration and weakness. Our previous findings supported the idea that dystrophin and associated proteins, absent or greatly reduced in DMD, are degraded in dystrophin-deficient muscle by the proteasomaldependent pathway. Indeed, treatment with the proteasome inhibitor MG-132 of skeletal muscles from mdx mice --a spontaneous mouse model of DMD-- as well as from DMD patients, effectively rescued the expression and correct cellular localization of dystrophin and associated proteins. These promising results led us to further explore the use of proteasome inhibitors as a therapy for DMD. Therefore, we directed our attention towards two new dipeptide boronic acid inhibitors blocking the proteasomal-dependent degradation pathway: Velcade (bortezomib or PS-341) and MLN273 (PS-273). The exciting aspect of this development is that these drugs have already progressed to preclinical and clinical trials, in different fields than muscular dystrophy. Indeed, Velcade has been already FDA-approved for treatment of multiple myeloma and its side effects had been already explored and managed. Promisingly, MLN273 is currently in the preclinical trial phase. Here, we test the effectiveness of Velcade and MLN273 by local injection into the gastrocnemius muscle of mdx mice. We show the rescue of expression and membrane localization of -dystroglycan, -dystroglycan, -sarcoglycan, and dystrophin after Velcade and MLN273 localized treatment, versus untreated (PBS only) mdx mice. Intriguingly, we also show that localized treatment with Velcade and MLN273 reduces the activation of Nuclear Factor-kappaB (NF-kB). Because NF-kB pathway has been shown to be involved in inflammation responses in myopathies and DMD, our current results may have important clinical implications. Clearly, more investigations are needed, but our results emphasize the effectiveness of the pharmacological approach as a potential treatment for Duchenne muscular dystrophy.
Authors
Gloria Bonuccelli
Thomas Jefferson University, Philadelphia, Pennsylvania
Federica Sotgia
Thomas Jefferson University, Philadelphia, Pennsylvania
Franco Capozza
Thomas Jefferson University, Philadelphia, Pennsylvania
Elisabetta Gazzerro
University of Genova, Genova, Italy
Carlo Minetti
University of Genova, Genova, Italy
Michael P. Lisanti
Thomas Jefferson University; Philadelphia, PA
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDF If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.