Evaluation of the Antigenicity of Black Restricted FVIII Haplotypes and Haplotype

Information

  • Research Project
  • 8591385
  • ApplicationId
    8591385
  • Core Project Number
    R41MD008156
  • Full Project Number
    1R41MD008156-01A1
  • Serial Number
    008156
  • FOA Number
    PA-12-089
  • Sub Project Id
  • Project Start Date
    9/18/2013 - 11 years ago
  • Project End Date
    8/31/2015 - 9 years ago
  • Program Officer Name
    TABOR, DERRICK C.
  • Budget Start Date
    9/18/2013 - 11 years ago
  • Budget End Date
    8/31/2015 - 9 years ago
  • Fiscal Year
    2013
  • Support Year
    01
  • Suffix
    A1
  • Award Notice Date
    9/18/2013 - 11 years ago
Organizations

Evaluation of the Antigenicity of Black Restricted FVIII Haplotypes and Haplotype

Evaluation of the Antigenicity of Black-Restricted Haplotypes of Factor VIII ABSTRACT About 30% of congenital Hemophilia A (HA) patients develop alloantibodies that neutralize the activity of replacement Factor (F) VIII proteins. Such patients, who are termed inhibitor patients, are typically treated with so called bypassing agents such as recombinant (r) FVIIa and FEIBA. Bypassing agents are more expensive and in general less effective than FVIII in fully controlling bleeding. Older HA inhibitor patients frequently have reduced mobility in comparison to patients who can be managed with FVIII. Although rare, acquired HA, caused by the sudden development of autoantibodies to the patient's own endogenous FVIII, is a life threatening condition. Acquired HA is treated with immune-response modulators, often in combination with bypassing agents. A FVIII therapeutic that possessed low reactivity with an inhibitor patient's extant antibodies and did not elicit an adverse immune response would be a significant advance over current therapies. We have identified several human FVIII haplotypes that we believe could represent low antigenic FVIII for some inhibitors patients. More importantly, we believe that using such haplotypes as starting templates may represent a fruitful approach to prepare a universal low antigenicity FVIII construct that would offer efficacy for most inhibitor patients. HA patients of Black African ancestry develop FVIII inhibitors twice as frequently as White HA patients. Resequencing studies of the FVIII gene (F8) have revealed four common nonsynonymous- single-nucleotide polymorphisms (ns-SNPs) that, together with two infrequent ns-SNPs, encode eight distinct wild-type FVIII proteins referred to as haplotype (H)1, H2, ..., H8. Individuals of Black African descent express all FVIII haplotypes except H6, which, to date, has only been identified in Asians. H3 and H4 FVIII occur only in the Black population. The ns-SNPs that define the H3 and H4 haplotypes reside within immunodominant epitopes of FVIII. This is intriguing as it suggests that these variations may impart differing reactivity with FVIII inhibitors. In collaboration with Dr. James Lillard, of the Morehouse School of Medicine, we plan to test the antigenicity of the naturally occurring Black restricted H3 and H4 FVIII protein haplotypes and a hybrid H3/H4 FVIII in this Phase 1 project.

IC Name
National Institute on Minority Health and Health Disparities
  • Activity
    R41
  • Administering IC
    MD
  • Application Type
    1
  • Direct Cost Amount
  • Indirect Cost Amount
  • Total Cost
    184545
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    375
  • Ed Inst. Type
  • Funding ICs
    NIMHD:129281\NHGRI:55264\
  • Funding Mechanism
    SBIR-STTR RPGs
  • Study Section
    ZRG1
  • Study Section Name
    Special Emphasis Panel
  • Organization Name
    HAPLOMICS, INC.
  • Organization Department
  • Organization DUNS
    609696690
  • Organization City
    LOS ANGELES
  • Organization State
    CA
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    900672326
  • Organization District
    UNITED STATES