Ultrasound-mediated gene delivery of factor VIII plasmids for hemophilia A gene therapy in mice.
Ultrasound-mediated gene delivery of factor VIII plasmids for hemophilia A gene therapy in mice.
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DOI：
10.1016/j.omtn.2022.01.006
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发表时间：
2022-03-08
期刊：
影响因子：
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通讯作者：
Miao CH
中科院分区：
文献类型：
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作者：
Song S;Lyle MJ;Noble-Vranish ML;Min-Tran DM;Harrang J;Xiao W;Unger EC;Miao CH
Gene therapy offers great promises for a cure of hemophilia A resulting from factor VIII (FVIII) gene deficiency. We have developed and optimized a non-viral ultrasound-mediated gene delivery (UMGD) strategy. UMGD of reporter plasmids targeting mice livers achieved high levels of transgene expression predominantly in hepatocytes. Following UMGD of a plasmid encoding human FVIII driven by a hepatocyte-specific promoter/enhancer (pHP-hF8/N6) into the livers of hemophilia A mice, a partial phenotypic correction was achieved in treated mice. In order to achieve persistent and therapeutic FVIII gene expression, we adopted a plasmid (pHP-hF8-X10) encoding an FVIII variant with significantly increased FVIII secretion. By employing an optimized pulse-train ultrasound condition and immunomodulation, the treated hemophilia A mice achieved 25%–150% of FVIII gene expression on days 1–7 with very mild transient liver damage, as indicated by a small increase of transaminase levels that returned to normal within 3 days. Therapeutic levels of FVIII can be maintained persistently without the generation of inhibitors in mice. These results indicate that UMGD can significantly enhance the efficiency of plasmid DNA transfer into the liver. They also demonstrate the potential of this novel technology to safely and effectively treat hemophilia A. Ultrasound-mediated gene delivery (UMGD) was demonstrated to efficiently transfer factor VIII plasmids driven by a hepatocyte-specific promoter/enhancer into the livers of hemophilia A mice. Persistent and therapeutic levels of factor VIII expression can be achieved, demonstrating the potential for UMGD to safely and effectively treat hemophilia A.
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影响因子：
11.1
作者：
Lofqvist, T;Nilsson, IM;Pettersson, H
通讯作者：
Pettersson, H
DOI：
10.1073/pnas.1914595117
发表时间：
2020-03-17
影响因子：
11.1
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影响因子：
2.9
作者：
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通讯作者：
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DOI：
10.1073/pnas.192219599
发表时间：
2002-10-01
影响因子：
11.1
作者：
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通讯作者：
Morgan, RA
DOI：
10.1038/mtm.2014.36
发表时间：
2014
期刊：
Molecular therapy. Methods & clinical development
影响因子：
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作者：
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