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CRISPR/Cas9-mediated somatic and germline gene correction to restore hemostasis in hemophilia B mice.

Abstract：

:Hemophilia B (HB) is an X-linked disorder caused by defects of F9 encoded coagulation factor IX, which is an ideal model for gene therapy. Most existing HB gene therapies are based on viral mediated gene supplementation, which could increase immunoreaction. In this study, CRISPR/Cas9 system was used for gene correction in an F9 mutant HB mouse model in both adult mice (in vivo) and in germline cells (ex vivo). In vivo, naked Cas9-sgRNA plasmid and donor DNA were delivered to HB mice livers to recover the mutation via hydrodynamic tail vein (HTV) injection. 62.5% of the HTV-treated mice showed a detectable gene correction (>1%) in the F9 alleles of hepatocytes, which was sufficient to remit the coagulation deficiency. Ex vivo, three different forms of Cas9 were microinjected into germline cells of HB mice to investigate their efficiency and safety in gene correction. Cas9 protein showed higher gene recovery rates, less embryo toxicity, and lower mosaic repair percentage, making it more suitable for germline gene therapy. Our study strongly supports that CRISPR/Cas9-mediated genome editing is feasible in gene therapy of genetic disorders.

journal_name

Hum Genet

journal_title

Human genetics

authors

Huai C,Jia C,Sun R,Xu P,Min T,Wang Q,Zheng C,Chen H,Lu D

doi

10.1007/s00439-017-1801-z

subject

Has Abstract

pub_date

2017-07-01 00:00:00

pages

875-883

issue

7

eissn

0340-6717

issn

1432-1203

pii

10.1007/s00439-017-1801-z

journal_volume

136

pub_type

杂志文章

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