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Sustained alpha‐sarcoglycan gene expression after gene transfer in limb‐girdle muscular dystrophy, type 2D
Author(s) -
Mendell Jerry R.,
RodinoKlapac 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.,
GastierFoster Julie M.,
Astbury Caroline,
Kota Janaiah,
Sahenk Zarife,
Walker Christopher M.,
Clark K. Reed
Publication year - 2010
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.22251
Subject(s) - muscular dystrophy , limb girdle muscular dystrophy , biology , gene expression , microbiology and biotechnology , gene , genetics , mutation
Abstract 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 × 10 11 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