Similar to human hemophilia B, canine hemophilia B has a sex-linked inheritance pattern, and no detectable circulating FIX exists in the plasma. Researchers have identified at least three colonies of hemophilia B dogs, each of which has a unique molecular FIX defect. Hemophilia B cairn terriers were identified in Toronto [
23] and have been maintained in Chapel Hill since 1966 [
24]. These animals have a point mutation that results in substitution of glutamic acid for glycine at AA 377 in the catalytic domain [
24]. Lhasa Apso dogs with hemophilia B, established in Auburn, Alabama [
25], carry a 5-bp deletion at nucleotides 772–776 and a C-to-T transition in the
FIX gene, resulting in a premature stop codon at AA 146 [
25]. A Labrador retriever colony at Cornell University, New York [
26], carries complete deletion of the canine
FIX gene. Chapel Hill and Auburn dogs have been used extensively for testing FIX products and gene therapy strategies. The Auburn dogs are prone to developing inhibitors to infused canine FIX [
27,
28]. Translational data produced from hemophilia B dogs have supported the development of long-acting FIX [
29,
30] with accompanying recent human clinical trials [
12,
31‐
34]. In contrast to the higher success ITI rate in hemophilia A, the ITI outcome in hemophilia B patients with FIX inhibitors is poor and research in this area remains in its infancy [
35]. Recently, an ITI strategy using AAV liver expression of a FIX variant, FIX-Padua was successfully applied to hemophilia B dogs prone to inhibitors. This strategy eradicated FIX inhibitor in dogs with pre-existing inhibitors [
34], suggesting its value in the development of ITI.