Bortezomib Partially Improves Laminin alpha 2 Chain-Deficient Muscular Dystrophy

作者：Korner Zandra; Fontes Oliveira Cibely C; Holmberg Johan; Carmignac Virginie; Durbeej Madeleine^*

来源：American Journal Of Pathology, 2014, 184(5): 1518-1528.

DOI：10.1016/j.ajpath.2014.01.019

Congenital muscular dystrophy, caused by mutations in LAMA2 (the gene encoding laminin alpha 2 chain), is a severe and incapacitating disease for which no therapy is yet available. We have recently demonstrated that proteasome activity is increased in Laminin a2 chain deficient muscle and that treatment with the nonpharmaceutical proteasome inhibitor MG-132 reduces muscle pathology in Laminin alpha 2 chain deficient dy(3K)/dy(3K) mice. Here, we explore the use of the selective and therapeutic proteasome inhibitor bortezomib (currently used for treatment of relapsed multiple myeloma and mantle cell Lymphoma) in dy(3K)/dy(3K) mice and in congenital muscular dystrophy type 1A muscle cells. Outcome measures included quantitative muscle morphology, gene and miRNA expression analyses, proteasome activity, motor activity, and survival. Bortezomib improved several histological hallmarks of disease, partially normalized miRNA expression (miR-1 and miR-133a), and enhanced body weight, Locomotion, and survival of dy(3K)/dy(3K) mice. In addition, bortezomib reduced proteasome activity in congenital muscular dystrophy type 1A myoblasts and myotubes. These findings provide evidence that the proteasome inhibitor bortezomib partially reduces laminin cx2 chain deficient muscular dystrophy. Investigation of the clinical efficacy of bortezomib administration in congenital muscular dystrophy type 1A clinical trials may be warranted.

• 出版日期2014-5