A factor IX-deficient mouse model for hemophilia B gene therapy

A factor IX-deficient mouse model for hemophilia B gene therapy

^*Laboratory of Genetics, and ^¶The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, P.O. Box 85800, San Diego, CA 92186-5800; and ^§Departments of Molecular and Experimental Medicine and of Vascular Biology, The Scripps Research Institute, La Jolla, CA 92037

Contributed by Inder M. Verma

Abstract

We have generated a mouse where the clotting factor IX (FIX) gene has been disrupted by homologous recombination. The FIX nullizygous (−/−) mouse was devoid of factor IX antigen in plasma. Consistent with the bleeding disorder, the factor IX coagulant activities for wild-type (+/+), heterozygous (+/−), and homozygous (−/−) mice were 92%, 53%, and <5%, respectively, in activated partial thromboplastin time assays. Plasma factor IX activity in the deficient mice (−/−) was restored by introducing wild-type murine FIX gene via adenoviral vectors. Thus, these factor IX-deficient mice provide a useful animal model for gene therapy studies of hemophilia B.

Footnotes

↵ † L.W. and M.Z. contributed equally to this paper.
↵ ‡ Present address: Istituto Tecnologie Biomediche Avanzate, Consiglio Nazionale delle Ricerche of Italy, via Ampere 56, 20131 Milan, Italy.
↵ ‖ To whom reprint requests should be addressed. e-mail: verma{at}salk.edu.
ABBREVIATIONS:

APTT,

activated partial thromboplastin time;

ES cell,

embryonic stem cell