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A small molecule integrin activator to enhance cord blood transplant

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 2R42HL129612-02
Agency Tracking Number: R42HL129612
Amount: $1,864,898.00
Phase: Phase II
Program: STTR
Solicitation Topic Code: NHLBI
Solicitation Number: PA18-575
Timeline
Solicitation Year: 2018
Award Year: 2020
Award Start Date (Proposal Award Date): 2020-03-15
Award End Date (Contract End Date): 2022-02-28
Small Business Information
2126 SHERIDAN ST
Houston, TX 77030-2108
United States
DUNS: 079364082
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 PETER VANDERSLICE
 (832) 355-9083
 pvanderslice@texasheart.org
Business Contact
 UPENDRA MARATHI
Phone: (832) 439-6612
Email: upendra@7hills.co
Research Institution
 TEXAS HEART INSTITUTE
 
BOX 20345, MC 3-116
HOUSTON, TX 77225-0345
United States

 Domestic Nonprofit Research Organization
Abstract

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.PROJECT NARRATIVE
The growing use of umbilical cord blood cells for bone marrow transplantation has allowed patients to be
treated that otherwise could not find a suitable donor. Finding a means to improve the rate of immune
reconstitution is critical to fully realize the potential of cord blood transplant and expanding its use to adult
patients. The studies proposed describe the use of a small molecule cell adhesion activator to facilitate the
engraftment rate of cord blood cells and thus decrease the time to immune reconstitution.

* Information listed above is at the time of submission. *

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