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- Title
Efficient recovery of dysferlin deficiency by dual adeno-associated vector-mediated gene transfer.
- Authors
Lostal, William; Bartoli, Marc; Bourg, Nathalie; Roudaut, Carinne; Bentaïb, Azeddine; Miyake, Katsuya; Guerchet, Nicolas; Fougerousse, Françoise; McNeil, Paul; Richard, Isabelle
- Abstract
Deficiency of the dysferlin protein presents as two major clinical phenotypes: limb-girdle muscular dystrophy type 2B and Miyoshi myopathy. Dysferlin is known to participate in membrane repair, providing a potential hypothesis to the underlying pathophysiology of these diseases. The size of the dysferlin cDNA prevents its direct incorporation into an adeno-associated virus (AAV) vector for therapeutic gene transfer into muscle. To bypass this limitation, we split the dysferlin cDNA at the exon 28/29 junction and cloned it into two independent AAV vectors carrying the appropriate splicing sequences. Intramuscular injection of the corresponding vectors into a dysferlin-deficient mouse model led to the expression of full-length dysferlin for at least 1 year. Importantly, systemic injection in the tail vein of the two vectors led to a widespread although weak expression of the full-length protein. Injections were associated with an improvement of the histological aspect of the muscle, a reduction in the number of necrotic fibers, restoration of membrane repair capacity and a global improvement in locomotor activity. Altogether, these data support the use of such a strategy for the treatment of dysferlin deficiency.
- Publication
Human molecular genetics, 2010, Vol 19, Issue 10, p1897
- ISSN
1460-2083
- Publication type
Journal Article
- DOI
10.1093/hmg/ddq065