A small molecule integrin activator to enhance cord blood transplant

Information

  • Research Project
  • 9907800
  • ApplicationId
    9907800
  • Core Project Number
    R42HL129612
  • Full Project Number
    2R42HL129612-02
  • Serial Number
    129612
  • FOA Number
    PA-18-575
  • Sub Project Id
  • Project Start Date
    9/1/2016 - 8 years ago
  • Project End Date
    2/28/2022 - 2 years ago
  • Program Officer Name
    OCHOCINSKA, MARGARET J
  • Budget Start Date
    3/15/2020 - 4 years ago
  • Budget End Date
    2/28/2021 - 3 years ago
  • Fiscal Year
    2020
  • Support Year
    02
  • Suffix
  • Award Notice Date
    3/7/2020 - 4 years ago
Organizations

A small molecule integrin activator to enhance cord blood transplant

PROJECT SUMMARY This proposal is in response to the parent announcement for Phase II STTR (R42) grant applications. Hematopoietic stem cell transplantation has become a preferred treatment for hematological malignancies and certain genetic disorders. Umbilical cord blood has become an appealing alternative to bone marrow or peripheral blood as a source of hematopoietic stem cells for transplant. Due to a less stringent HLA match requirement, cord blood transplant has allowed patients to be treated that otherwise could not find a suitable donor. Unfortunately, there are fewer stem cells in these preparations which results in delayed rates of immunological reconstitution. This can lead to a higher incidence of opportunistic infections which increases the rate of graft failures and transplant related mortalities. Finding a means to improve the rate of immune reconstitution with cord blood transplants would translate to improved outcomes as well as broader applicability to adult patients. Efforts to improve the rate of engraftment of cord blood cells include targeting the cell adhesion cascade which mediates cell homing, extravasation and retention in the bone marrow. This process is coordinated through the function of chemokines as well as the selectin and integrin families of cell adhesion molecules. Promising results have been generated by treating the cells ex-vivo to improve the function of the selectin- and chemokine-mediated processes. A drawback to these preconditioning steps is they require additional time, expertise and expense. As yet the integrins have not been targeted due to a lack of suitable reagents. We have developed a unique small molecule that can activate integrins on cord blood cells, facilitating their interaction with their counter-receptors in the bone marrow. This compound can enhance all phases of the adhesion cascade including cell rolling, firm adhesion, and migration. It can be dosed independently of the cells and is inexpensive to synthesize on a large-scale. This would have an advantage over other technologies as no preconditioning or manipulations of the cells would be required meaning a more affordable and universally translatable therapy. We have demonstrated proof-of-concept in our phase I studies that dosing 7HP349 following transplant of human CD34+ cord blood cells into NOD-SCID mice leads to increased engraftment of CD34+ cells in the bone marrow and increased CD45+ cell counts in peripheral blood. Our phase II proposal includes aims to refine the dosing schedule and preclinical formulation and toxicity studies required to file an Investigational New Drug application with the Food and Drug Administration.

IC Name
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
  • Activity
    R42
  • Administering IC
    HL
  • Application Type
    2
  • Direct Cost Amount
  • Indirect Cost Amount
  • Total Cost
    935957
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    837
  • Ed Inst. Type
  • Funding ICs
    NHLBI:935957\
  • Funding Mechanism
    SBIR-STTR RPGs
  • Study Section
    ZRG1
  • Study Section Name
    Special Emphasis Panel
  • Organization Name
    7 HILLS PHARMA, LLC
  • Organization Department
  • Organization DUNS
    079364082
  • Organization City
    HOUSTON
  • Organization State
    TX
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    770302108
  • Organization District
    UNITED STATES