通过剪接体介导的RNA反式剪接对甲型血友病小鼠进行表型校正。

Phenotype correction of hemophilia A mice by spliceosome-mediated RNA trans-splicing.

作者信息

Chao Hengjun, Mansfield S Gary, Bartel Robert C, Hiriyanna Suja, Mitchell Lloyd G, Garcia-Blanco Mariano A, Walsh Christopher E

机构信息

Department of Medicine, Mt. Sinai School of Medicine, New York, New York 10029, USA.

出版信息

Nat Med. 2003 Aug;9(8):1015-9. doi: 10.1038/nm900. Epub 2003 Jul 6.

DOI:10.1038/nm900

PMID:12847523

Abstract

Conventional gene therapy of hemophilia A relies on the transfer of factor VIII (FVIII; encoded by the F8 gene) cDNA. We carried out spliceosome-mediated RNA trans-splicing (SMaRT) to repair mutant FVIII mRNA. A pre-trans-splicing molecule (PTM) corrected endogenous FVIII mRNA in F8 knockout mice with the hemophilia A phenotype, producing sufficient functional FVIII to correct the hemophilia A phenotype. This is the first description of phenotypic correction of a genetic defect by RNA repair in a knockout animal model. Our results indicate the feasibility of using SMaRT to repair RNA for the treatment of genetic diseases.

摘要

A型血友病的传统基因治疗依赖于VIII因子（FVIII；由F8基因编码）cDNA的转移。我们进行了剪接体介导的RNA反式剪接（SMaRT）以修复突变的FVIII mRNA。一种前体反式剪接分子（PTM）纠正了具有A型血友病表型的F8基因敲除小鼠中的内源性FVIII mRNA，产生了足够的功能性FVIII来纠正A型血友病表型。这是在基因敲除动物模型中通过RNA修复对遗传缺陷进行表型纠正的首次描述。我们的结果表明使用SMaRT修复RNA用于治疗遗传疾病的可行性。