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 L McNeil, Isabelle Richard

Research output: Contribution to journalArticle

86 Citations (Scopus)

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

Fingerprint

Dependovirus
Complementary DNA
Protein Deficiency
Muscles
Injections
Membranes
Intramuscular Injections
Locomotion
Genes
Tail
Veins
Exons
Phenotype
Therapeutics
Proteins
Miyoshi myopathy
Type 2B Limb-girdle muscular dystrophy

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Lostal, W., Bartoli, M., Bourg, N., Roudaut, C., Bentaïb, A., Miyake, K., ... 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

Efficient recovery of dysferlin deficiency by dual adeno-associated vector-mediated gene transfer. / Lostal, William; Bartoli, Marc; Bourg, Nathalie; Roudaut, Carinne; Bentaïb, Azeddine; Miyake, Katsuya; Guerchet, Nicolas; Fougerousse, Françoise; McNeil, Paul L; Richard, Isabelle.

In: Human Molecular Genetics, Vol. 19, No. 10, 13.02.2010, p. 1897-1907.

Research output: Contribution to journalArticle

Lostal, W, Bartoli, M, Bourg, N, Roudaut, C, Bentaïb, A, Miyake, K, Guerchet, N, Fougerousse, F, McNeil, PL & Richard, I 2010, 'Efficient recovery of dysferlin deficiency by dual adeno-associated vector-mediated gene transfer', Human Molecular Genetics, vol. 19, no. 10, pp. 1897-1907. https://doi.org/10.1093/hmg/ddq065
Lostal, William ; Bartoli, Marc ; Bourg, Nathalie ; Roudaut, Carinne ; Bentaïb, Azeddine ; Miyake, Katsuya ; Guerchet, Nicolas ; Fougerousse, Françoise ; McNeil, Paul L ; Richard, Isabelle. / Efficient recovery of dysferlin deficiency by dual adeno-associated vector-mediated gene transfer. In: Human Molecular Genetics. 2010 ; Vol. 19, No. 10. pp. 1897-1907.
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