# Optimization of small molecule integrin activators to enhance cord blood transplant

> **NIH NIH R33** · TEXAS HEART INSTITUTE · 2022 · $547,028

## Abstract

PROJECT SUMMARY
This proposal is in response to the funding opportunity announcement RFA-HL-20-027 for the Catalyze: Product
Definition for Small Molecules and Biologics - Preliminary Product/Lead Series Identification (R33 - Clinical Trial
Not Allowed) granting mechanism. 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 family of small molecules that can activate integrins on cord blood cells,
facilitating their interaction with their counter-receptors in the bone marrow. We have demonstrated proof-of-
concept using a representative member of the family that dosing such a compound 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. These compounds can be dosed independently of the cells
and are typically 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. Although promising, our lead compound suffers from low oral bioavailability
in part due to it being metabolized by CYP3A4. These issues make it less attractive for cord blood transplant
due to potential drug-drug interactions as well as the multi-day dosing regimen that will likely be required based
on preclinical animal models. This R33 grant proposal includes aims to address the structural alerts for CYP3A4
activit...

## Key facts

- **NIH application ID:** 10368757
- **Project number:** 1R33HL161778-01
- **Recipient organization:** TEXAS HEART INSTITUTE
- **Principal Investigator:** Ronald J Biediger
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $547,028
- **Award type:** 1
- **Project period:** 2022-02-15 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10368757

## Citation

> US National Institutes of Health, RePORTER application 10368757, Optimization of small molecule integrin activators to enhance cord blood transplant (1R33HL161778-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10368757. Licensed CC0.

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