Efficient recovery of dysferlin deficiency by dual adeno-associated vector-mediated gene transfer

William Lostal, Marc Bartoli, Nathalie Bourg, Carinne Roudaut, Azeddine Bentaïb, Katsuya Miyake, Nicolas Guerchet, Françoise Fougerousse, Paul McNeil, Isabelle Richard

Research output: Contribution to journalArticle

96 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1897-1907
Number of pages11
JournalHuman Molecular Genetics
Volume19
Issue number10
DOIs
StatePublished - Feb 13 2010

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Lostal, W., Bartoli, M., Bourg, N., Roudaut, C., Bentaïb, A., Miyake, K., Guerchet, N., Fougerousse, F., McNeil, P., & Richard, I. (2010). Efficient recovery of dysferlin deficiency by dual adeno-associated vector-mediated gene transfer. Human Molecular Genetics, 19(10), 1897-1907. https://doi.org/10.1093/hmg/ddq065