PMID: 9639513Jun 25, 1998Paper

Targeted inactivation of the coagulation factor IX gene causes hemophilia B in mice.

Blood
R K KunduE M Gordon

Abstract

Hemophilia B is a leading target for gene therapy because current therapy is not optimal. Hence, a murine model of factor IX (F. IX) deficiency was generated to develop gene therapy strategies for hemophilia B. A targeting vector was created by replacing a 3.2-kb segment of the gene encompassing the catalytic domain with a phosphoglycerokinase promoter-driven neomycin resistant (neor) gene cassette. The transfected embryonic stem cell clones generated chimeric male mice, and germ line transmission of the inactivated F. IX gene was observed in their offsprings. Southern analysis confirmed the mutant genotype in hemizygous male and carrier female mice. F. IX transcripts were not detected in liver RNA isolated from hemizygous mice, and lower levels of F. IX mRNA were noted in carrier female mice when compared with those of normal litter mates. As expected, the mean F. IX coagulant titer of affected male mice was 2.8 U/dL (n = 10), while the mean F. IX titer of carrier female mice was 35 U/dL (n = 14), compared with 69 U/dL (n = 9) for the normal female mice and 92 U/dL (n = 22) for normal male and female litter mates. Further, the tail bleeding time of hemizygous mice was markedly prolonged (>3 hours) compared with those of normal...Continue Reading

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