A phase I trial of adeno-associated virus serotype 1-γ-sarcoglycan gene therapy for limb girdle muscular dystrophy type 2C - Université d'Évry Access content directly
Journal Articles Brain - A Journal of Neurology Year : 2012

A phase I trial of adeno-associated virus serotype 1-γ-sarcoglycan gene therapy for limb girdle muscular dystrophy type 2C

France Herson
  • Function : Author
Anthony Behin
  • Function : Author
  • PersonId : 887996
Rim Amouri
  • Function : Author
Hafedh Haddad
  • Function : Author
Muriel Audit
  • Function : Author
Marie Montus
  • Function : Author
Carole Masurier
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  • PersonId : 858686
Bernard Gjata
  • Function : Author
Mustapha Cheraï
  • Function : Author
Yves Hogrel
  • Function : Author
Yves Allenbach
François Lemoine
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David Klatzmann
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  • PersonId : 860339
Richard Mulligan
  • Function : Author
Didier Caizergues
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Olivier Benveniste
Jean-Yves Hogrel
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  • PersonId : 901910
H. Lee Sweeney
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Abstract

γ-Sarcoglycanopathy or limb girdle muscular dystrophy type 2C is an untreatable disease caused by autosomal recessively inherited mutations of the γ-sarcoglycan gene. Nine non-ambulatory patients (two males, seven females, mean age 27 years; range 16-38 years) with del525T homozygous mutation of the γ-sarcoglycan gene and no γ-sarcoglycan immunostaining on muscle biopsy were divided into three equal groups to receive three escalating doses of an adeno-associated virus serotype 1 vector expressing the human γ-sarcoglycan gene under the control of the desmin promoter, by local injection into the extensor carpi radialis muscle. The first group received a single injection of 3 × 10(9) viral genomes in 100 µl, the second group received a single injection of 1.5 × 10(10) viral genomes in 100 µl, and the third group received three simultaneous 100-µl injections at the same site, delivering a total dose of 4.5 × 10(10) viral genomes. No serious adverse effects occurred during 6 months of follow-up. All nine patients became adeno-associated virus serotype 1 seropositive and one developed a cytotoxic response to the adeno-associated virus serotype 1 capsid. Thirty days later, immunohistochemical analysis of injected-muscle biopsy specimens showed γ-sarcoglycan expression in all three patients who received the highest dose (4.7-10.5% positively stained fibres), while real-time polymerase chain reaction detected γ-sarcoglycan messenger RNA. In one patient, γ-sarcoglycan protein was detected by western blot. For two other patients who received the low and intermediate doses, discrete levels of γ-sarcoglycan expression (<1% positively stained fibres) were also detectable. Expression of γ-sarcoglycan protein can be induced in patients with limb girdle muscular dystrophy type 2C by adeno-associated virus serotype 1 gene transfer, with no serious adverse effects.

Dates and versions

hal-02179399 , version 1 (10-07-2019)

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France Herson, Faycal Hentati, Aude Rigolet, Anthony Behin, Norma Beatriz Romero, et al.. A phase I trial of adeno-associated virus serotype 1-γ-sarcoglycan gene therapy for limb girdle muscular dystrophy type 2C. Brain - A Journal of Neurology , 2012, 135 (2), pp.483-492. ⟨10.1093/brain/awr342⟩. ⟨hal-02179399⟩
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