Recombinant micro-genes and dystrophin viral vectors

An effective gene therapy for Duchenne muscular dystrophy ideally relies on the ability to provide long-term expression to muscle tissue of the missing protein, dystrophin. Early work in the mdx mouse using a 6.3 kb mini-dystrophin cDNA, carried out in either adenoviral or retroviral vectors was gen...

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Bibliographic Details
Published in:Neuromuscular disorders : NMD 2002-10, Vol.12, p.S40-S44
Main Authors: Dickson, G, Roberts, M.L, Wells, D.J, Fabb, S.A
Format: Article
Language:English
Subjects:
Adeno-retroviral vector
Adenoviridae - genetics
Animals
Cytoskeletal Proteins - genetics
Dependovirus - genetics
DNA, Recombinant
Duchenne muscular dystrophy
Dystrophin - genetics
Gene Expression
Gene Transfer Techniques
Genes, Viral
Genetic Therapy - methods
Genetic Vectors
Humans
Membrane Proteins - genetics
Mice
Mice, Inbred mdx
Micro-dystrophin constructs
Muscle, Skeletal - pathology
Muscular Dystrophy, Duchenne - genetics
Muscular Dystrophy, Duchenne - therapy
Retroviridae - genetics
Utrophin
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Summary:An effective gene therapy for Duchenne muscular dystrophy ideally relies on the ability to provide long-term expression to muscle tissue of the missing protein, dystrophin. Early work in the mdx mouse using a 6.3 kb mini-dystrophin cDNA, carried out in either adenoviral or retroviral vectors was generally successful, however, expression was only transient. In an attempt to remedy this problem, two approaches are being investigated. The first of these is a hybrid vector system that combines the efficacy of gene transfer into skeletal muscle of adenoviral vectors with the long-term stability of retroviral vectors. The second utilises the inherently efficient transducing properties and stability of the adeno-associated viral delivery system. Using highly truncated micro-dystrophin cDNAs we have shown that both vector systems were able to restore dystrophin and dystrophin-associated protein expression at the plasma membrane of mdx mice for prolonged periods of time. Additionally, evaluation of central nucleation indicated a significant inhibition of degenerative dystrophic muscle pathology. These studies suggest that hybrid adenoviral–retroviral and adeno-associated viral vectors are capable of ameliorating dystrophic pathology at the cellular level and as such are useful tools in the development of a gene therapy for Duchenne muscular dystrophy.
ISSN:0960-8966
1873-2364
DOI:10.1016/S0960-8966(02)00080-9