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 jointscauses 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.
Thesaurus Terms: Abate;African;African American;Aftercare;Amino Acids;Antibodies;Antibody Formation;Antigens;Autoimmune Process;Base;Biological Assay;Bypass;Carbodiimides;Childhood;Chronic;Clinical;Clinically Relevant;Clip;Coagulation Process;Collaborations;Cost;Coupled;Design;Design And Construction;Development;Disease;Doctor Of Philosophy;Dose;Effective Therapy;Engineering;Epitopes;Ethylenes;European;Experience;Experimental Autoimmune Encephalomyelitis;F Factor;Family Suidae;Fda Approved;Frequencies (Time Pattern);Genetic;Germany;Glycolic-Lactic Acid Polyester;Haplotypes;Hemophilia A;Hemorrhage;Heterogeneity;Human;Immune Response;Immune Tolerance;Immunogenic;Immunogenicity;In Vivo;Indium;Individual;Infusion Procedures;Inhibitor/Antagonist;Intravenous;Isoantibodies;Joints;Laboratories;Letters;Methionine;Methods;Modeling;Morbidity - Disease Rate;Morehouse School Of Medicine;Mouse Model;Multiple Sclerosis;Mus;Myelin;Novel;Novel Strategies;Orthopedic Surgery Procedures;Pain;Pathway Interactions;Patients;Peptides;Pharmaceutical Preparations;Pharmacogenomics;Physicians;Plasma;Positioning Attribute;Preempt;Preparation;Prevent;Procedures;Protein Aminoacid Sequence;Proteins;Protocols Documentation;Public Health Relevance;Recombinants;Reconstitution;Replacement Therapy;Reporting;Research Personnel;Response;Risk;Site;Source;Structure;Symptoms;T Cell Response;T-Lymphocyte Epitopes;Tail;Techniques;Testing;Time;Valine;
