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Blood, Vol. 93 No. 6 (March 15), 1999:
pp. 1875-1881
The Rhesus Macaque as an Animal Model for Hemophilia B Gene Therapy
Jay N. Lozier,
Mark E. Metzger,
Robert E. Donahue, and
Richard A. Morgan
From the National Human Genome Research Institute and the National
Heart, Lung, and Blood Institute, Bethesda, MD.
We have determined the 2905 nucleotide sequence of the rhesus
macaque factor IX complementary DNA (cDNA) and found it to be greater
than 95% identical to that of the human factor IX cDNA. The cDNA has a
large 3' untranslated region like the human cDNA, but unlike the
human cDNA has two polyadenylation sites 224 nucleotides apart that are
used for transcription of the messenger RNA. The deduced amino acid
sequence is greater than 97% identical to that of human factor IX,
differing in only 11 of 461 amino acids in the complete precursor
protein. We found a single silent polymorphism in the nucleotide
sequence at the third position of the codon for asparagine at position
167 in the secreted protein (AAC/AAT). All residues subject to
posttranslational modifications in the human protein are also found in
the rhesus factor IX sequence. The high degree of homology between the
rhesus and human factor IX proteins suggested the possibility that the
human factor IX protein might be nonimmunogenic in the rhesus. We
tested the immunogenicity of human factor IX in three rhesus macaques
by repeated intravenous injections of monoclonal antibody-purified,
plasma-derived human factor IX over the course of more than a year and
assessed the recovery and half-life of the infused protein, as well as
in vitro indicators of antihuman factor IX antibodies. Human factor IX recovery and half-life remained unchanged over the course of a year in
the three animals studied, and aPTT mixing studies showed no evidence
for neutralizing antihuman factor IX antibodies. An outbred, nonhuman
primate model that permits assessment of the level and duration of
factor IX expression as well as vector safety would complement the use
of other (mouse and canine) hemophilia B animal models in current use
for the development of gene therapy for hemophilia B.
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