Goal 1: Promote Human Health

Re-examining Antigenicity of Rare Blood Disease Proteins

What specific roles do protein glycosylation and protein complex formation on stable and activated cellular membranes play in inherent immunogenicity and antibody formation to life-saving therapies for rare blood disorders?

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Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Inhibitory alloantibody formation to critical life-saving therapies impedes effective replacement therapy in up to 30-40% of children and adults with congenital blood diseases, thereby significantly increasing the complications of the underlying disease. For children with hemophilia A, this treatment complication has significantly limited the impact of the last 20 years of therapeutic advances in product efficacy and safety. Discovery science in this area has focused on the relationship between the immune response and treatment circumstances, and the epitope specificity of the targeted immune response. However, this scientific pathway to discovery has not yielded the critical mechanistic data required to inform effective prevention strategies. Recent advances in our understanding of the co-factors for immunogenicity, the biochemistry of coagulation factor complex formation on cellular membranes, glycobiology and gene transfer must now converge to create a potential platform for exploring new paradigms of immunogenicity, and thus leading to new strategies for inducing tolerance to future new therapeutics in hemophilia.

Feasibility and challenges of addressing this CQ or CC :

A recent workshop sponsored by the National Hemophilia Foundation highlighted the threat to novel therapies for hemophilia as well as curative gene therapy from the unsolved problem of replacement protein or gene product antigenicity. However recent advances in our understanding of the co-factors for immunogenicity, the biochemistry of coagulation factor complex formation on cellular membranes, glycobiology and gene transfer, can now converge to create a potential platform for exploring new paradigms of immunogenicity, and thus leading to new strategies for inducing tolerance to future new therapeutic. NHLBI leadership and collaboration with NIAID is needed to bring this combined expertise to bear on the understanding and prevention of this most significant complication of hemophilia therapy.

Name of idea submitter and other team members who worked on this idea : NHLBI Staff

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Idea No. 332