1. LH / Q3012R Molecular Biology, Immunology, & Genetics of Coagulation Factors Jay Lozier, M.D., Ph.D. Principal Investigator Report to the Blood Products Advisory Committee, September 29, 2005 on February 25, 2005 LH Site Visit

2. LH Regulatory Issues: Inhibitors to Factors VIII/IX Public Health Impact/Mission Relevance Antibodies to coagulation factors prevent the use of therapeutic products in ~20% of patients with hemophilia.Antibodies to coagulation factors prevent the use of therapeutic products in ~20% of patients with hemophilia. Understanding factors that control whether patients make antibodies to therapeutic products is important for evaluation of their immunogenicity.Understanding factors that control whether patients make antibodies to therapeutic products is important for evaluation of their immunogenicity. LH / Q3012R Lozier, PI

3. Research Questions/Problems 1.Are there genetic factors in patients that influence inhibitors? 2.Are there animal models in which to study the problem? 3.How can we leverage FDA resources to study this problem using outside resources and collaborators? LH / Q3012R Lozier, PI

4. Mouse Animal Models Using genetically well-characterized inbred mouse strains we have shown: Using genetically well-characterized inbred mouse strains we have shown: –MHC genes, T-cell receptors, and zinc-  - 2-glycoprotein 1 genes influence the antibody response to human factor VIII –MHC genes and to a lesser extent, cytokine genes (IL10, Interferon-  ) control the antibody response to human factor IX. Lozier, et al., Blood 2005;105:1029-1035. LH / Q3012R Lozier, PI

5. Hemophilia A Dog Model –The Chapel Hill hemophilia A dogs have a gene inversion identical to that in ~40% of humans with severe hemophilia A. –The bleeding phenotype is identical to human hemophilia A. –The dogs can & do make inhibitors when treated with dog factor VIII. Lozier et al, PNAS 2002;99:12991-12996 The Chapel Hill hemophilia A dogs are an ideal model in which to study mechanisms for inhibitor antibodies: LH / Q3012R Lozier, PI

6. Future Directions: Pharmacogenomics I We will test the hypothesis that genes identified in the mouse have similar influence on inhibitor antibodies in hemophilia dogs, and the hypothesis that differences in the normal factor VIII protein can influence development of inhibitors in hemophilia A. LH / Q3012R Lozier, PI

7. Future Directions: Pharmacogenomics II We will test the hypothesis that candidate genes identified in the mouse have similar influence on inhibitor antibodies in humans with hemophilia A. LH / Q3012R Lozier, PI

8. Jay Lozier, M.D., Ph.D., Principal InvestigatorJay Lozier, M.D., Ph.D., Principal Investigator Nahid Tayebi, Ph.D., Staff FellowNahid Tayebi, Ph.D., Staff Fellow Laura Wood, B.S., BiologistLaura Wood, B.S., Biologist Pei Zhang, M.D., Collaborator (DH/LPD)Pei Zhang, M.D., Collaborator (DH/LPD) Timothy Nichols, M.D., Collaborator (UNC)Timothy Nichols, M.D., Collaborator (UNC) James Goedert, M.D., Collaborator (NCI)James Goedert, M.D., Collaborator (NCI) Marjory Brooks, D.V.M., Collaborator (Cornell)Marjory Brooks, D.V.M., Collaborator (Cornell) Personnel/Collaborators LH / Q3012R Lozier, PI