Hematopoietic stem cell transplantation (HSCT) has become a standard care for the treatment of many hematologic malignancies and non-malignant diseases such as bone marrow failure and immunodeficiency syndromes. Currently, myeloablative or irradiative conditioning regimens are used for enhancing HSC engraftment in transplantation, but they are often associated with significant morbidity and mortality, particularly in patients under severe clinical or pathological stress. In addition, in many clinical cases only limited numbers of HSCs are available for transplant. Improving efficiency of BM niche access will improve HSCT outcomes by increasing donor chimerism in clinical settings where stem cell numbers are limiting and recipients are fragile, e.g. in cord blood or gene therapy transplants. As an important intracellular signal transducer of multiple cell stimuli required for HSC maintenance, including signaling from receptor tyrosine kinase c-Kit, chemokine receptor CXCR4 and adhesion receptor integrins, the Rho GTPase Cdc42 plays crucial roles in regulating cell actin cytoskeleton, integrin-mediated adhesion, and chemokine induced directional migration. Structure- function information of Cdc42 derived by structural, biochemical, and mouse model studies have paved the way for the design, identification, and validation of Cdc42-specific inhibitors for translational applications. This Phase I SBIR focuses on developing a novel therapeutic regimen by utilizing CASIN, the Cdc42-targeting small molecule, for opening BM niches to allow donor HSC engraftment, and establishing that Cdc42 targeting can be applied to enhancing human hematopoietic stem cell engraft efficiency in preclinical mouse models without myeloablation or irradiation. Such a conditioning regimen will have immediate commercial value in autologous or human cord blood transplantation therapy where the HSC number is often limited and a significant increase in engraftment will have significant clinical impact. Should the proposed work prove successful, future studies will further develop CASIN and its derivatives in large animal PK/PD and toxicity tests and move for commercialization of this highly promising and innovative technology.

Public Health Relevance

Studies of the cell signaling molecule Cdc42 regulation and physiological function in blood stem cells have laid out the foundation to translate our knowledge to therapies in hematopoietic stem cell transplantation. The proposal will validate the proof-of-principle of a novel non-myeloablative approach for facilitating HSC engraftment and apply the method to enhance autologous and allo-transplantation efficiency in preclinical models. Successful application of this approach to bone marrow transplantation may lead to a novel therapeutics benefiting future cell therapy and transplantation practices.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
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Special Emphasis Panel (ZRG1-VH-F (10))
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Mitchell, Phyllis
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P2, Inc.
United States
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