Retargeting mobile group II introns to repair mutant genes

被引:15
作者
Jones, JP
Kierlin, MN
Coon, RG
Perutka, J
Lambowitz, AM
Sullenger, BA [1 ]
机构
[1] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA
[2] Duke Univ, Med Ctr, Dept Mol Genet & Microbiol, Durham, NC 27710 USA
[3] Univ Texas, Inst Mol & Cellular Biol, Dept Chem & Biochem, Austin, TX 78712 USA
[4] Univ Texas, Sch Biol Sci, Sect Mol Genet & Microbiol, Austin, TX 78712 USA
基金
美国国家卫生研究院;
关键词
D O I
10.1016/j.ymthe.2005.01.014
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Retroposable elements such as retroviral and lentiviral vectors have been employed for many gene therapy applications. Unfortunately, such gene transfer vectors integrate genes into many different DNA sequences and unintended integration of the vector near a growth-promoting gene can engender pathological consequences. For example, retroviral vector-mediated gene transfer induced leukemia in 2 of 11 children treated for severe combined immunodeficiency, raising significant safety issues for gene transfer strategies that cannot be targeted to specific sequences. Here, we examine the use of a mobile retroposable genetic element that can be targeted to introduce therapeutic sequences site specifically into mutant genes. The data demonstrate that the mobile group II intron from Lactococcus lactis can be targeted to insert into and repair mutant lacZ (approved gene symbol GLB1) and β-globin (approved gene symbol HBB) genes with high efficiency and fidelity in model systems in bacteria. These results suggest that these mobile genetic elements represent a novel class of agents for performing targeted genetic repair.
引用
收藏
页码:687 / 694
页数:8
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