Since FIX expression in platelets is effective for hemophilia B, efficacy in the presence of inhibitory antibodies to FIX was not achieved and emphasized the importance of VWF to the efficacy of platelet FVIII expression.
In a landmark study published in 2011, Nathwani et al demonstrated successful conversion of severe hemophilia B to mild or moderate disease in 6 adult males who underwent intravenous infusion of an adeno-associated viral (AAV) vector expressing factor IX.
High-purity factor IX concentrates are available and are the treatment of choice for patients with haemophilia B in the absence of a source of recombinant factor IX.
Pharmacokinetics of a novel extended half-life glycoPEGylated factor IX, nonacog beta pegol (N9-GP) in previously treated patients with haemophilia B: results from two phase 3 clinical trials.
Although factor IX activity was only slightly reduced (mean 88% standard) and factor IX antigen was normal, mean activated factor VII in patients was strikingly reduced to 34% of that in controls, a level similar to that found in haemophilia B.
The disease is characterized by a normal ox-brain prothrombin time, normal levels of the vitamin-K dependent clotting factors VII and X and a proportional reduction of factor IX activity and antigen levels all of which is consistent with the cross-reacting material negative form of haemophilia B.
By amplification and direct sequencing, 51 single base substitutions were found in the transcribed sequence of the factor IX genes of patients from 50 distinct families with hemophilia B.
However, a synonymous mutation c.459G>A (Val107Val) was clinically reported to result in mild haemophilia B (FIX coagulant activity 15%-20% of normal).
Our studies indicate that whereas large structural factor IX gene defects predispose hemophilia B patients to developing an anti-factor IX inhibitor, the development of an inhibitor can be associated with other defects of the factor IX gene.
Our findings imply that assay discrepancy occurs for factor IX activity and that both type of assays are needed for a correct diagnosis and classification of haemophilia B.
Immune responses following gene transfer of coagulation factor IX (FIX) for the treatment of the bleeding disorder hemophilia B has been extensively investigated in multiple animal models.
Factor IXAlabama is a variant factor IX molecule responsible for a clinically moderate form of hemophilia B. Twenty-five kilobases (kb) of the variant gene, including seven exons coding for the structural protein, were cloned and characterized.
As models we selected F9 nonsense mutations with readthrough-favorable features affecting the pre-peptide and pro-peptide regions of coagulation factor IX (FIX), which cause hemophilia B (HB).
This patient also developed an antibody to factor IX during replacement therapy, which suggests that deletion of the factor IX gene is not necessary for development of the antibody in hemophilia B patients.
In bleeding CRM<sup>-</sup> hemophilia B mice, the times to first clot at a saphenous vein injury site after the infusions of the FIX agents are significantly different, at FIX<sub>WT</sub> < FIX<sub>FC</sub> < FIX<sub>Alb</sub> Dysfunctional forms of FIX, however, circulate in the majority of patients with hemophilia B (CRM<sup>+</sup>).