About 30% of congenital Hemophilia A (HA) patients develop alloantibodies that neutralize the activity of replacement Factor (F) VIII proteins. Among African American HA patients, the frequency of inhibitor formation is much higher;about 50%. Inhibitor patients are typically treated with bypassing agents. Bypassing agents are more expensive and less effective than FVIII in fully controlling bleeding. Chronic bleeding into joints causes inhibitor patients to require more orthopedic surgeries and to experience reduced mobility, in comparison to HA patients who can be managed with replacement FVIII. Despite the introduction of some 40 FVIII products, the rate of inhibitor formation has remained constant since the 1970s. Undergoing a lengthy, arduous and very expensive therapy, known as immune tolerance induction (ITI), is the only means available to eradicate inhibitors in HA patients. The amount of FVIII required for ITI and the intensity of the treatment result in costs ranging from $500,000-$1,000,000 per inhibitor patient. Unfortunately, ITI fails in about 30% of patients. At least one clinical report suggests ITI may have reduced efficacy in African American HA inhibitor patients. Our team of investigators is developing a personalized, pharmacogenomic approach for treating HA. This approach may be applied to curb the onset of inhibitor formation and to eradicate extant inhibitors. A cornerstone of this approach involves determining structural differences between the HA patient's endogenous FVIII protein and candidate replacement FVIII products. The majority of HA patients make a substantially complete FVIII molecule and are expected to be tolerized to their endogenous FVIII. It follows that for most HA patients, elements in replacement FVIII having the potential to trigger an immune response, termed T cell epitopes, reside in one or more very discrete sections of the replacement FVIII, and are susceptible to identification. It has recently been reported that antigen specific tolerance may be achieved through exploitation of a salvage pathway. Specifically, intravenous delivery of microparticles coated with peptides derived from myelin, abated an autoimmune attack of """"""""self-myelin"""""""" in a mouse model of multiple sclerosis. In this project, we will evaluate whether a similar approach has utility for preventing or abating the immune response to FVIII therapy. We will do so by administering FVIII constructs designed to be immunogenic to a hemophilic mouse that has been engineered to be tolerant to human FVIII. The FVIII immunogens will be fully functional FVIII molecules in which peptide sequences from porcine FVIII have been substituted for human sequence at sites of FVIII known to be the target of the immune response to FVIII. As in HA patients, the FVIII proteins will control bleeding in the model until high titer inhibitors emerge. We will test the hypothesis that intravenous delivery of microparticles coated with peptides identical in structure to the T cell epitopes engineered into our FVIII immunogens, will preempt or mute the immune response to the immunogenic FVIII proteins in this clinically relevant model of HA.

Public Health Relevance

Hemophilia A (HA) is a genetic bleeding disorder caused by inadequate activity of a protein needed for clot formation called FVIII. Administering replacement FVIII is the preferred therapy for HA and is effective for many HA patients. Some HA patients make antibodies that render the replacement FVIII ineffective. They have to be treated with more expensive and less effective therapies. In this project we plan to evaluate new methods to avoid rejection of FVIII by HA patients;and to reduce existing antibodies against FVIII so that more HA patients can benefit from treatment with FVIII.

National Institute of Health (NIH)
National Institute on Minority Health and Health Disparities (NIMHD)
Small Business Technology Transfer (STTR) Grants - Phase I (R41)
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Special Emphasis Panel (ZRG1)
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Tabor, Derrick C
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Haplomics, Inc.
Los Angeles
United States
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