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Targeted Inactivation of the Coagulation Factor IX Gene Causes
Hemophilia B in Mice
Ramendra Krishna Kundu,
Frank Sangiorgi,
Lang-Ying Wu,
Kotoku Kurachi,
W. French Anderson,
Robert Maxson, and
Erlinda M. Gordon
From the USC Gene Therapy Laboratories, the Division of
Hematology-Oncology, the Departments of Pediatrics and Biochemistry and
Molecular Biology, Childrens Hospital Los Angeles, Los Angeles; the
University of Southern California School of Medicine, Los Angeles, CA;
and the Department of Human Genetics, University of Michigan, Ann
Arbor.
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 and carrier female
litter mates (15 to 20 minutes). Seven of 19 affected male mice died of
exsanguination after tail snipping, and two affected mice died of
umbilical cord bleeding. Currently, there are 10 affected mice
surviving at 4 months of age. Aside from the factor IX defect, the
carrier female and hemizygous male mice had no liver pathology by
histologic examination, were fertile, and transmitted the F. IX gene
mutation in the expected Mendelian frequency. Taken together, we have
generated a F. IX knockout mouse for evaluation of novel gene therapy
strategies for hemophilia B.
Blood, Vol. 92 No. 1 (July 1), 1998:
pp. 168-174
© 1998 by The American Society of Hematology.
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