Sustained alpha-sarcoglycan gene expression after gene transfer in limb-girdle muscular dystrophy, type 2D.
Sustained alpha-sarcoglycan gene expression after gene transfer in limb-girdle muscular dystrophy, type 2D.
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DOI：
10.1002/ana.22251
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发表时间：
2010-11
影响因子：
11.2
通讯作者：
Clark, K. Reed
中科院分区：
文献类型：
--
作者：
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
The aim of this study was to attain long-lasting alpha-sarcoglycan gene expression in LGMD2D subjects mediated by adeno-associated virus (AAV) gene transfer under control of a muscle specific promoter (tMCK) rAAV1.tMCK.hSGCA (3.25 × 1011 vg) was delivered to the extensor digitorum brevis (EDB) muscle of three 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 reported to the oversight committee. Persistent alpha-sarcoglycan gene expression was achieved for six months in two of three LGMD2D subjects. Markers for muscle fiber transduction other than alpha-sarcoglycan included expression of major histocompatability complex I (MHC 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 TUNEL 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 (ELISpot) on the second day post gene injection. This was in clear distinction to other participants with satisfactory gene expression. 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 clinical trial was evident, and the potential for reversal of disease was displayed.
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DOI：
10.1186/1479-0556-6-14
发表时间：
2008-10-15
期刊：
Genetic vaccines and therapy
影响因子：
--
作者：
Pacak, Christina A;Conlon, Thomas;Byrne, Barry J
通讯作者：
Byrne, Barry J
DOI：
10.1038/mt.2009.254
发表时间：
2010-01
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
通讯作者：
--
影响因子：
4
作者：
Carrie, A;Piccolo, F;Jeanpierre, M
通讯作者：
Jeanpierre, M
影响因子：
5.4
作者：
Chen, CL;Jensen, RL;Johnson, PR
通讯作者：
Johnson, PR
影响因子：
2.7
作者：
Bonnemann, Carsten G;Finkel, Richard S
通讯作者：
Finkel, Richard S