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Laminins and Congenital Muscular Dystrophy - From a Mouse Model to Gene Therapy of Laminin alpha2 chain deficiency?

Gawlik, Kinga LU (2006)
Abstract
Gene therapy holds great promise for treating many genetic diseases, including muscular dystrophies. Mutations in the gene encoding laminin alpha2 chain ? an extracellular protein prominently expressed in the neuromuscular system ? cause a severe neuromuscular disorder: congenital muscular dystrophy type 1A (MDC1A). Currently, there is no treatment for MDC1A. Preclinical studies are the first step in testing genetic approaches for future gene therapy in humans. In the course of my research, I focused on a genetically manipulated mouse model of MDC1A, investigating whether the transgenic introduction of laminin ?1 chain into laminin alpha2 chain deficient tissues would prevent the development of disease symptoms.



The... (More)
Gene therapy holds great promise for treating many genetic diseases, including muscular dystrophies. Mutations in the gene encoding laminin alpha2 chain ? an extracellular protein prominently expressed in the neuromuscular system ? cause a severe neuromuscular disorder: congenital muscular dystrophy type 1A (MDC1A). Currently, there is no treatment for MDC1A. Preclinical studies are the first step in testing genetic approaches for future gene therapy in humans. In the course of my research, I focused on a genetically manipulated mouse model of MDC1A, investigating whether the transgenic introduction of laminin ?1 chain into laminin alpha2 chain deficient tissues would prevent the development of disease symptoms.



The overexpression of laminin alpha1 chain greatly improved overall health and normalized the life span of laminin alpha2 chain deficient animals. Laminin alpha1 chain, which in the adult body is expressed only in a few epithelial tissues, functionally compensated for laminin alpha2 chain loss in muscle, peripheral nervous system and testis, correcting their morphology and restoring their function. Moreover, laminin alpha1 chain proved to be essential for the normal expression levels of laminin receptors dystroglycan and integrin alpha7 in laminin alpha2 chain deficient muscle. I suggest that our preclinical studies with laminin alpha1 chain transgene may serve as a paradigm for gene therapy of congenital muscular dystrophy in patients. (Less)
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author
supervisor
opponent
  • Professor Ruegg, Marcus, University of Basel, Switzerland
organization
publishing date
type
Thesis
publication status
published
subject
keywords
laminin, muscular dystrophy, gene therapy, Histology, cytochemistry, histochemistry, tissue culture, Histologi, cytokemi, histokemi, vävnadskultur, Genetics, cytogenetics, cytogenetik, Skeleton, muscle system, rheumatology locomotion, Skelett, muskelsystem, reumatologi, Genetik
pages
85 pages
publisher
Faculty of Medicine, Department of Experimental Medical Science
defense location
Biomedical Centre, Sölvegatan 19 GK Salen
defense date
2006-12-09 09:00:00
ISBN
91-85559-55-5
language
English
LU publication?
yes
additional info
Kinga Gawlik, Yuko Miyagoe-Suzuki, Peter Ekblom, Shin'ichi Takeda and Madeleine Durbeej. 2004. Laminin alpha1 chain reduces muscular dystrophy in laminin alpha2 chain deficient mice Human Molecular Genetics, vol 13 pp 1775-1784.
Mattias Häger, Kinga Gawlik, Alexander Nyström, Takako Sasaki and Madeleine Durbeej. 2005. Laminin alpha1 chain corrects male infertility caused by absence of laminin alpha2 chain American Journal of Pathology, vol 167 pp 823-833.
Kinga Gawlik, Jia-Yi Li, Åsa Petersen and Madeleine Durbeej. 2006. Laminin alpha1 chain improves laminin alpha2 chain deficient peripheral neuropathy Human Molecular Genetics, vol 15 pp 2690-2700.
Kinga Gawlik, Ulrike Mayer, Kristina Blomberg, Arnoud Sonnenberg, Peter Ekblom and Madeleine Durbeej. 2006. Laminin alpha1 chain mediated reduction of laminin alpha2 chain deficient muscular dystrophy involves integrin alpha7 beta1 and dystroglycan FEBS Letters, vol 580 pp 1759-1765.
id
43b4913c-c07f-4f10-b4ab-6b1da9141096 (old id 547637)
date added to LUP
2016-04-01 16:41:01
date last changed
2018-11-21 20:43:24
@phdthesis{43b4913c-c07f-4f10-b4ab-6b1da9141096,
  abstract     = {{Gene therapy holds great promise for treating many genetic diseases, including muscular dystrophies. Mutations in the gene encoding laminin alpha2 chain ? an extracellular protein prominently expressed in the neuromuscular system ? cause a severe neuromuscular disorder: congenital muscular dystrophy type 1A (MDC1A). Currently, there is no treatment for MDC1A. Preclinical studies are the first step in testing genetic approaches for future gene therapy in humans. In the course of my research, I focused on a genetically manipulated mouse model of MDC1A, investigating whether the transgenic introduction of laminin ?1 chain into laminin alpha2 chain deficient tissues would prevent the development of disease symptoms.<br/><br>
<br/><br>
The overexpression of laminin alpha1 chain greatly improved overall health and normalized the life span of laminin alpha2 chain deficient animals. Laminin alpha1 chain, which in the adult body is expressed only in a few epithelial tissues, functionally compensated for laminin alpha2 chain loss in muscle, peripheral nervous system and testis, correcting their morphology and restoring their function. Moreover, laminin alpha1 chain proved to be essential for the normal expression levels of laminin receptors dystroglycan and integrin alpha7 in laminin alpha2 chain deficient muscle. I suggest that our preclinical studies with laminin alpha1 chain transgene may serve as a paradigm for gene therapy of congenital muscular dystrophy in patients.}},
  author       = {{Gawlik, Kinga}},
  isbn         = {{91-85559-55-5}},
  keywords     = {{laminin; muscular dystrophy; gene therapy; Histology; cytochemistry; histochemistry; tissue culture; Histologi; cytokemi; histokemi; vävnadskultur; Genetics; cytogenetics; cytogenetik; Skeleton; muscle system; rheumatology locomotion; Skelett; muskelsystem; reumatologi; Genetik}},
  language     = {{eng}},
  publisher    = {{Faculty of Medicine, Department of Experimental Medical Science}},
  school       = {{Lund University}},
  title        = {{Laminins and Congenital Muscular Dystrophy - From a Mouse Model to Gene Therapy of Laminin alpha2 chain deficiency?}},
  year         = {{2006}},
}