A phase I trial of adeno-associated virus serotype 1-γ-sarcoglycan gene therapy for limb girdle muscular dystrophy type 2C
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2012 |
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| Erschienen: |
2012 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:135 |
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| Enthalten in: |
Brain : a journal of neurology - 135(2012), Pt 2 vom: 15. Feb., Seite 483-92 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Herson, Serge [VerfasserIn] |
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| Links: |
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| Themen: |
Clinical Trial, Phase I |
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| Anmerkungen: |
Date Completed 27.04.2012 Date Revised 15.11.2012 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1093/brain/awr342 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM214516210 |
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| 100 | 1 | |a Herson, Serge |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A phase I trial of adeno-associated virus serotype 1-γ-sarcoglycan gene therapy for limb girdle muscular dystrophy type 2C |
| 264 | 1 | |c 2012 | |
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| 500 | |a Date Completed 27.04.2012 | ||
| 500 | |a Date Revised 15.11.2012 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Clinical Trial, Phase I | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Sarcoglycans |2 NLM | |
| 700 | 1 | |a Hentati, Faycal |e verfasserin |4 aut | |
| 700 | 1 | |a Rigolet, Aude |e verfasserin |4 aut | |
| 700 | 1 | |a Behin, Anthony |e verfasserin |4 aut | |
| 700 | 1 | |a Romero, Norma B |e verfasserin |4 aut | |
| 700 | 1 | |a Leturcq, France |e verfasserin |4 aut | |
| 700 | 1 | |a Laforêt, Pascal |e verfasserin |4 aut | |
| 700 | 1 | |a Maisonobe, Thierry |e verfasserin |4 aut | |
| 700 | 1 | |a Amouri, Rim |e verfasserin |4 aut | |
| 700 | 1 | |a Haddad, Hafedh |e verfasserin |4 aut | |
| 700 | 1 | |a Audit, Muriel |e verfasserin |4 aut | |
| 700 | 1 | |a Montus, Marie |e verfasserin |4 aut | |
| 700 | 1 | |a Masurier, Carole |e verfasserin |4 aut | |
| 700 | 1 | |a Gjata, Bernard |e verfasserin |4 aut | |
| 700 | 1 | |a Georger, Christophe |e verfasserin |4 aut | |
| 700 | 1 | |a Cheraï, Mustapha |e verfasserin |4 aut | |
| 700 | 1 | |a Carlier, Pierre |e verfasserin |4 aut | |
| 700 | 1 | |a Hogrel, Jean-Yves |e verfasserin |4 aut | |
| 700 | 1 | |a Herson, Ariane |e verfasserin |4 aut | |
| 700 | 1 | |a Allenbach, Yves |e verfasserin |4 aut | |
| 700 | 1 | |a Lemoine, François M |e verfasserin |4 aut | |
| 700 | 1 | |a Klatzmann, David |e verfasserin |4 aut | |
| 700 | 1 | |a Sweeney, H Lee |e verfasserin |4 aut | |
| 700 | 1 | |a Mulligan, Richard C |e verfasserin |4 aut | |
| 700 | 1 | |a Eymard, Bruno |e verfasserin |4 aut | |
| 700 | 1 | |a Caizergues, Didier |e verfasserin |4 aut | |
| 700 | 1 | |a Voït, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Benveniste, Olivier |e verfasserin |4 aut | |
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