title: A phase I trial of adeno-associated virus serotype 1-γ-sarcoglycan gene therapy for limb girdle muscular dystrophy type 2C.
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.
authors.affiliation: Service de Médecine Interne 1, Groupe Hospitalier Pitié-Salpêtrière, 47-83, boulevard de l'Hôpital, 75651 Paris Cedex 13, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Herson
authors.forename: Faycal
authors.initials: F
authors.lastname: Hentati
authors.forename: Aude
authors.initials: A
authors.lastname: Rigolet
authors.forename: Anthony
authors.initials: A
authors.lastname: Behin
authors.forename: Norma B
authors.initials: NB
authors.lastname: Romero
authors.forename: France
authors.initials: F
authors.lastname: Leturcq
authors.forename: Pascal
authors.initials: P
authors.lastname: Laforêt
authors.forename: Thierry
authors.initials: T
authors.lastname: Maisonobe
authors.forename: Rim
authors.initials: R
authors.lastname: Amouri
authors.forename: Hafedh
authors.initials: H
authors.lastname: Haddad
authors.forename: Muriel
authors.initials: M
authors.lastname: Audit
authors.forename: Marie
authors.initials: M
authors.lastname: Montus
authors.forename: Carole
authors.initials: C
authors.lastname: Masurier
authors.forename: Bernard
authors.initials: B
authors.lastname: Gjata
authors.forename: Christophe
authors.initials: C
authors.lastname: Georger
authors.forename: Mustapha
authors.initials: M
authors.lastname: Cheraï
authors.forename: Pierre
authors.initials: P
authors.lastname: Carlier
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Hogrel
authors.forename: Ariane
authors.initials: A
authors.lastname: Herson
authors.forename: Yves
authors.initials: Y
authors.lastname: Allenbach
authors.forename: François M
authors.initials: FM
authors.lastname: Lemoine
authors.forename: David
authors.initials: D
authors.lastname: Klatzmann
authors.forename: H Lee
authors.initials: HL
authors.lastname: Sweeney
authors.forename: Richard C
authors.initials: RC
authors.lastname: Mulligan
authors.forename: Bruno
authors.initials: B
authors.lastname: Eymard
authors.forename: Didier
authors.initials: D
authors.lastname: Caizergues
authors.forename: Thomas
authors.initials: T
authors.lastname: Voït
authors.forename: Olivier
authors.initials: O
authors.lastname: Benveniste
mesh_terms: D000293:Adolescent; D000328:Adult; D000229:Dependovirus / Q000235:genetics / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D049031:Sarcoglycans / Q000235:genetics* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D049031:Sarcoglycans