MicroRNA-206 Downregulation Improves Therapeutic Gene Expression and Motor Function in mdx Mice.
MicroRNA-206 Downregulation Improves Therapeutic Gene Expression and Motor Function in mdx Mice.
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DOI：
10.1016/j.omtn.2018.05.011
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发表时间：
2018-09-07
期刊：
影响因子：
--
通讯作者：
Xiao X
中科院分区：
文献类型：
--
作者：
Bulaklak K;Xiao B;Qiao C;Li J;Patel T;Jin Q;Li J;Xiao X
杜氏肌营养不良症（DMD）是一种由肌营养不良蛋白基因突变引起的严重肌肉萎缩症。已经开发了许多基因疗法来替代或修复有缺陷的肌营养不良蛋白基因；然而，这些治疗不能恢复全长蛋白或完全解决营养不良症状。继发性病理机制，如功能性缺血和纤维化，被认为会加剧原发性缺陷，并导致营养不良肌肉的严重肌肉变性。利用替代治疗基因或“增强基因”（如VEGFA和utrophin）的替代疗法寻求解决这些次要机制，并在mdx小鼠中显示出令人印象深刻的益处。骨骼肌特异性microRNA miR-206在营养不良肌肉中过度表达，抑制已知增强基因的表达。因此，我们的目的是确定miR-206是否通过抑制有益基因的表达而导致营养不良病理。在这里，我们发现aav介导的miR-206诱饵靶点的表达可以有效下调miR-206的表达，并增加成熟mdx肌肉中内源性治疗基因的表达。此外，治疗显著改善mdx小鼠的运动功能和营养不良病理。总之，我们已经确定了一个促成营养不良表型的因素，并描述了一种新的治疗DMD的途径。
Duchenne muscular dystrophy (DMD) is a severe muscle-wasting disorder caused by a mutation in the dystrophin gene. Numerous gene therapies have been developed to replace or repair the defective dystrophin gene; however, these treatments cannot restore the full-length protein or completely resolve dystrophic symptoms. Secondary pathological mechanisms, such as functional ischemia and fibrosis, are thought to exacerbate the primary defect and cause the profound muscle degeneration found in dystrophic muscle. Surrogate therapies utilizing alternative therapeutic genes, or “booster genes,” such as VEGFA and utrophin, seek to address these secondary mechanisms and have shown impressive benefit in mdx mice. A skeletal muscle-specific microRNA, miR-206, is particularly overexpressed in dystrophic muscle and inhibits the expression of known booster genes. Thus, we aimed to determine if miR-206 contributes to dystrophic pathology by repressing beneficial gene expression. Here, we show that AAV-mediated expression of a miR-206 decoy target effectively downregulated miR-206 expression and increased endogenous therapeutic gene expression in mature mdx muscle. Furthermore, treatment significantly improved motor function and dystrophic pathology in mdx mice. In summary, we have identified a contributing factor to the dystrophic phenotype and characterized a novel therapeutic avenue for DMD.
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影响因子：
9.9
作者：
Nelson, Michael D.;Rader, Florian;Victor, Ronald G.
通讯作者：
Victor, Ronald G.
DOI：
10.1007/978-1-61779-370-7_5
发表时间：
2011-01-01
期刊：
ADENO-ASSOCIATED VIRUS: METHODS AND PROTOCOLS
影响因子：
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作者：
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影响因子：
4.8
作者：
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通讯作者：
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DOI：
10.1083/jcb.200911036
发表时间：
2010-09-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Chen JF;Tao Y;Li J;Deng Z;Yan Z;Xiao X;Wang DZ
通讯作者：
Wang DZ
影响因子：
168.9
作者：
Cirak, Sebahattin;Arechavala-Gomeza, Virginia;Guglieri, Michela;Feng, Lucy;Torelli, Silvia;Anthony, Karen;Abbs, Stephen;Garralda, Maria Elena;Bourke, John;Wells, Dominic J.;Dickson, George;Wood, Matthew J. A.;Wilton, Steve D.;Straub, Volker;Kole, Ryszard;Shrewsbury, Stephen B.;Sewry, Caroline;Morgan, Jennifer E.;Bushby, Kate;Muntoni, Francesco
通讯作者：
Muntoni, Francesco