Efficient recovery of dysferlin deficiency by dual adeno-associated vector-mediated gene transfer - Archive ouverte HAL
Article Dans Une Revue Human Molecular Genetics Année : 2010

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

William Lostal
  • Fonction : Auteur
Marc Bartoli
Nathalie Bourg
Carinne Roudaut
Azéddine Bentaib
  • Fonction : Auteur
  • PersonId : 938605
Katsuya Miyake
  • Fonction : Auteur
Nicolas Guerchet
  • Fonction : Auteur
Paul Mcneil
  • Fonction : Auteur
Isabelle Richard

Résumé

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.

Dates et versions

hal-01610036 , version 1 (04-10-2017)

Identifiants

Citer

William Lostal, Marc Bartoli, Nathalie Bourg, Carinne Roudaut, Azéddine Bentaib, et al.. Efficient recovery of dysferlin deficiency by dual adeno-associated vector-mediated gene transfer. Human Molecular Genetics, 2010, 19 (10), pp.1897-1907. ⟨10.1093/hmg/ddq065⟩. ⟨hal-01610036⟩

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