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Sustained alpha-sarcoglycan gene expression after gene transfer in limb-girdle muscular dystrophy, type 2D

Mendell, Jerry R. ; Rodino-Klapac, Louise R. ; Rosales, Xiomara Q. ; Coley, Brian D. ; Galloway, Gloria ; Lewis, Sarah ; Malik, Vinod ; Shilling, Chris ; Byrne, Barry J. ; Conlon, Thomas ; Campbell, Katherine J. ; Bremer, William G. ; Taylor, Laura E. ; Flanigan, Kevin M. ; Gastier-Foster, Julie M. ; Astbury, Caroline ; Kota, Janaiah ; Sahenk, Zarife ; Walker, Christopher M. ; Clark, K. Reed

Annals of neurology, 2010-11, Vol.68 (5), p.629-638 [Periódico revisado por pares]

Hoboken: Wiley Subscription Services, Inc., A Wiley Company

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Título:
Sustained alpha-sarcoglycan gene expression after gene transfer in limb-girdle muscular dystrophy, type 2D
Autor: Mendell, Jerry R. ; Rodino-Klapac, Louise R. ; Rosales, Xiomara Q. ; Coley, Brian D. ; Galloway, Gloria ; Lewis, Sarah ; Malik, Vinod ; Shilling, Chris ; Byrne, Barry J. ; Conlon, Thomas ; Campbell, Katherine J. ; Bremer, William G. ; Taylor, Laura E. ; Flanigan, Kevin M. ; Gastier-Foster, Julie M. ; Astbury, Caroline ; Kota, Janaiah ; Sahenk, Zarife ; Walker, Christopher M. ; Clark, K. Reed
Assuntos: Adeno-associated virus ; Adolescent ; Adult ; Apoptosis ; Biological and medical sciences ; Child ; Dependovirus - genetics ; Diseases of striated muscles. Neuromuscular diseases ; Female ; Gene Expression ; Gene Transfer Techniques - adverse effects ; Genetic Therapy - methods ; Genetic Vectors - immunology ; Humans ; Leukocytes, Mononuclear - metabolism ; Male ; Medical sciences ; Muscle, Skeletal - metabolism ; Muscular Dystrophies, Limb-Girdle - metabolism ; Muscular Dystrophies, Limb-Girdle - therapy ; Neurology ; Sarcoglycans - genetics ; Sarcoglycans - metabolism
É parte de: Annals of neurology, 2010-11, Vol.68 (5), p.629-638
Notas: istex:A7CA39416BC099D56AEE32449933B55DAA1F6AC2
ark:/67375/WNG-RB6KNZW9-8
ArticleID:ANA22251
This study has been registered at Clinicaltrials.gov as NCT00494195.
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Descrição: Objective: The aim of this study was to attain long‐lasting alpha‐sarcoglycan gene expression in limb‐girdle muscular dystrophy, type 2D (LGMD2D) subjects mediated by adeno‐associated virus (AAV) gene transfer under control of a muscle specific promoter (tMCK). Methods: rAAV1.tMCK.hSGCA (3.25 × 1011 vector genomes) was delivered to the extensor digitorum brevis muscle of 3 subjects with documented SGCA mutations via a double‐blind, randomized, placebo controlled trial. Control sides received saline. The blind was not broken until the study was completed at 6 months and all results were reported to the oversight committee. Results: Persistent alpha‐sarcoglycan gene expression was achieved for 6 months in 2 of 3 LGMD2D subjects. Markers for muscle fiber transduction other than alpha‐sarcoglycan included expression of major histocompatibility complex I, increase in muscle fiber size, and restoration of the full sarcoglycan complex. Mononuclear inflammatory cells recruited to the site of gene transfer appeared to undergo programmed cell death, demonstrated by terminal deoxynucleotide transferase–mediated deoxyuridine triphosphate nick‐end labeling and caspase‐3 staining. A patient failing gene transfer demonstrated an early rise in neutralizing antibody titers and T‐cell immunity to AAV, validated by enzyme‐linked immunospot on the second day after gene injection. This was in clear distinction to other participants with satisfactory gene expression. Interpretation: The findings of this gene replacement study in LGMD2D subjects have important implications not previously demonstrated in muscular dystrophy. Long‐term, sustainable gene expression of alpha‐sarcoglycan was observed following gene transfer mediated by AAV. The merit of a muscle‐specific tMCK promoter, not previously used in a clinical trial, was evident, and the potential for reversal of disease was displayed. ANN NEUROL 2010;68:629–638
Editor: Hoboken: Wiley Subscription Services, Inc., A Wiley Company
Idioma: Inglês

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Sustained alpha-sarcoglycan gene expression after gene transfer in limb-girdle muscular dystrophy, type 2D

Hoboken: Wiley Subscription Services, Inc., A Wiley Company

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