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Bortezomib Partially Improves Laminin α2 Chain-Deficient Muscular Dystrophy.

Körner, Zandra LU ; Fontes Oliveira, Cibely LU ; Holmberg, Johan K LU ; Carmignac, Virginie LU and Durbeej-Hjalt, Madeleine LU (2014) In American Journal of Pathology 184(5). p.1518-1528
Abstract
Congenital muscular dystrophy, caused by mutations in LAMA2 (the gene encoding laminin α2 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 α2 chain-deficient muscle and that treatment with the nonpharmaceutical proteasome inhibitor MG-132 reduces muscle pathology in laminin α2 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... (More)
Congenital muscular dystrophy, caused by mutations in LAMA2 (the gene encoding laminin α2 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 α2 chain-deficient muscle and that treatment with the nonpharmaceutical proteasome inhibitor MG-132 reduces muscle pathology in laminin α2 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 α2 chain-deficient muscular dystrophy. Investigation of the clinical efficacy of bortezomib administration in congenital muscular dystrophy type 1A clinical trials may be warranted. (Less)
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organization
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type
Contribution to journal
publication status
published
subject
in
American Journal of Pathology
volume
184
issue
5
pages
1518 - 1528
publisher
American Society for Investigative Pathology
external identifiers
  • pmid:24631023
  • wos:000335284400025
  • scopus:84899502670
ISSN
1525-2191
DOI
10.1016/j.ajpath.2014.01.019
language
English
LU publication?
yes
id
5bf98dad-6b2e-4673-8af2-be0573e0acba (old id 4383212)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/24631023?dopt=Abstract
date added to LUP
2014-04-03 15:15:16
date last changed
2017-04-23 03:14:57
@article{5bf98dad-6b2e-4673-8af2-be0573e0acba,
  abstract     = {Congenital muscular dystrophy, caused by mutations in LAMA2 (the gene encoding laminin α2 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 α2 chain-deficient muscle and that treatment with the nonpharmaceutical proteasome inhibitor MG-132 reduces muscle pathology in laminin α2 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 α2 chain-deficient muscular dystrophy. Investigation of the clinical efficacy of bortezomib administration in congenital muscular dystrophy type 1A clinical trials may be warranted.},
  author       = {Körner, Zandra and Fontes Oliveira, Cibely and Holmberg, Johan K and Carmignac, Virginie and Durbeej-Hjalt, Madeleine},
  issn         = {1525-2191},
  language     = {eng},
  number       = {5},
  pages        = {1518--1528},
  publisher    = {American Society for Investigative Pathology},
  series       = {American Journal of Pathology},
  title        = {Bortezomib Partially Improves Laminin α2 Chain-Deficient Muscular Dystrophy.},
  url          = {http://dx.doi.org/10.1016/j.ajpath.2014.01.019},
  volume       = {184},
  year         = {2014},
}