Inhibitors Article by: Braden Waters B.Sc.H (dal), PhD (Candidate) Queen’s University, Kingston, ON Lillicrap Lab June 22, 2007 Approximately 25% of hemophilia A patients will have their treatment deleteriously affected by the development neutralizing anti-factor VIII antibodies (“inhibitors”)1. Inhibitors render the current FVIII infusion therapy useless, forcing patients to use expensive inhibitor by-passing reagents to treat bleeding, and at some point, they may also require some form of immunomodulatory intervention to generate immunological tolerance to FVIII. I first met a patient with severe hemophilia A and inhibitors while at campy IV-Y in Washington State the summer of 2002. This young fellow was a 10-year-old named Dillion. For approximately 90% of this week-long trip, which was filled with a myriad of activities that boys love to participate in, Dillon was confined to a wheel chair. Dillon’s target joints were the ankles, and I still remember vividly how bloated-swollen they were. Or, how he would walk stiffed-legged, with his ankles fused from the swelling and knees locked straight to compensate, baring weight on the heel as so many hemophiliacs must do, to participate in camp activities despite (or in spite of) of the cries of his camp counselors to remain in the chair. Inhibitors in hemophilia A patients develop because these individuals lack central tolerance to FVIII. Central tolerance is a process in normal individuals where FVIII-reactive T and B lymphocytes (i.e. white blood cells) will be eliminated2,3. Thus the patient’s immune system views the infused FVIII as a foreign antigen, and this results in the activation of these lymphocytes and an immune response against FVIII1. For the past 30 years, this condition has been treated with immune tolerance induction (ITI) therapy, the repeated intravenous administration of massive doses of FVIII4,5. There are several variations on the dose and frequency of dosing but the success rate of ITI is ~75%. Despite this success, ITI is extremely expensive and can require greater than 2 years to achieve tolerance6. This is often coupled to difficulties such as the requirement of continuous venous access, often a challenge in young boys; strict adherence to the ITI protocol; and in some cases, indefinite FVIII prophylaxis following successful ITI to maintain tolerance. In addition, the cost of products to treat bleeding episodes is enormous (in some cases, hundreds of thousands of dollars to treat a single bleeding episode)7. Thus, novel inhibitor immunomodulatory therapies that are both fast-acting and economical are very badly needed. I found Dillon’s condition very troubling, and my experiences with Dillon (and all the people at camp IV-Y) have been an immense source of motivation for my research. For the past 16 months I have developed and have begun to test several novel pre-clinical approaches for tolerance induction to FVIII in hemophilia A mice. These include use of the T cell depleting anti-CD3 monoclonal antibody (I presented this work to the ISTH conference in Geneva this July), nasal administration of the FVIII-A2 and FVIII-C2 domains, and a gene transfer approach to tolerogenically express FVIII in the nasal epithelium. These are ambitious projects; however, we believe that the current treatments available for inhibitor patients are unsatisfactory, and that these projects, if translated to clinical practice, may have significant economical impact and may greatly improve the lifestyle of these patients.
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