Laminins and Congenital Muscular Dystrophy - From a Mouse Model to Gene Therapy of Laminin alpha2 chain deficiency?
Author
Summary, in English
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.
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.
Department/s
Publishing year
2006
Language
English
Document type
Dissertation
Publisher
Faculty of Medicine, Department of Experimental Medical Science
Topic
- Basic Medicine
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
Status
Published
Research group
- Muscle Biology
Supervisor
ISBN/ISSN/Other
- ISBN: 91-85559-55-5
Defence date
9 December 2006
Defence time
09:00
Defence place
Biomedical Centre, Sölvegatan 19 GK Salen
Opponent
- Marcus Ruegg (Professor)