Early Translational I
$1 093 500
This is a multidisciplinary translational research project with the aim of translating latest discoveries of the role of chemokine-receptor interactions in directing stem cell migration toward injury sites in the brain and heart for regenerative repairs into novel stem cell-based regenerative medicine. We have already identified promising experiment drug candidate that will be further developed through this project into new therapeutics for the treatment of heart diseases such as stroke as well as CNS and cardiac injuries. The underlying hypothesis for this proposal is that the homing of human neural stem cells (hNSCs) to, as well as engagement and interaction with, sites of the central nervous system (CNS) injury is essential for regenerative repair process and that synthetic molecules (drugs) with activity of promoting such stem cell homing and engagement will lead to new stem cell-based therapies for CNS injuries caused by heart diseases such as stroke. Here in this application we propose to apply our technology and expertise in synthetic chemistry and stem cell biology to generate highly potent and specific small molecule agents capable of triggering and directing stem cell homing to the CNS injury sites for regenerative repairs.
Statement of Benefit to California:
Injuries in the brain and heart affect many patients in California. As the disease model studied in this particular project is representative of heart disease (stroke) and many other brain diseases, information and development candidates obtained from this project will have wide implication in studying and treating a number of brain and heart diseases. This project will lead to the translation of our technologies into new therapeutic strategies for clinically repairing injuries in the brain and heart such as those caused by stroke.
The goal of this effort is to develop small molecule therapies for repairing damage due to diseases or injuries affecting the central nervous system (CNS). To achieve these ends, the applicants will combine synthetic chemistry and molecular modeling approaches to design and optimize novel agonists for CXCR4, a chemokine receptor that has been implicated in promoting cell survival, proliferation, and migration. A series of specific aims have been devised to test the hypothesis that such agonists would be capable of triggering and directing neural stem cell (NSC) homing to CNS injury sites for regeneration. First, the applicants propose to synthesize and optimize current small molecule development candidates for activating CXCR4-mediated stem cell homing to neural injury sites. Next, the biological activity and therapeutic potential of these agonists will be evaluated in a series of in vitro assays and in vivo models of CNS injury. Finally, the applicants will subject the most promising leads to a panel of toxicological and pharmacokinetic analyses. Reviewers agreed that the proposed research addresses an important need and could have a potentially high impact on the field of neuroregenerative medicine. CXCR4, which is expressed on NSCs, represents a promising new route for therapy, and there are currently no drugs on the market that target this factor for selective activation. In general, reviewers were very impressed with the overall rationale of the proposed effort. Reviewers discussed a number of strengths and weaknesses in the experimental design, in terms of design and feasibility of the research plan. First, the heart of Aim 1 is based in classical drug discovery methods, the feasibility of which has been demonstrated repeatedly. Furthermore, the applicants presented robust preliminary data that indicated they are well positioned to succeed in this regard. Finally, the multidisciplinary expertise of the collaborating investigators appeared particularly well suited for a project of this nature. While confident that the investigators would identify agonists with appropriate activity, reviewers were uncertain that the therapeutic potential of these molecules would be realized. One particular concern was whether such molecules would be sufficiently stable and selective to be of practical use. Some reviewers felt that the applicants should have addressed this possibility by offering a more thorough characterization of the peptide moieties and how they could be modified for maximal utility. Other reviewers wondered whether the observed selectivity demonstrated by the leading candidate would be sufficient to prevent unwanted effects due to activation of CCR5, an alternative chemokine receptor that showed a small difference in affinity. One reviewer noted that an agonist of CXCR4 has been already been described, and this molecule could have been valuable for demonstrating proof of concept. Additional questions were raised about the proposed site of action for the development candidates. The practicality of delivering therapies directly to an infarct, as described in the proposal, seemed unreasonable in a clinical setting. Perhaps the most serious concerns were raised about the proposed animal methodologies, which are considered the backbone of this project. These experiments were poorly described and lacking in details, and it was unclear whether the appropriate expertise was in place to manage an analysis of this complexity. While the co-investigator offered a letter of support, there was no mention of the stroke model, thus raising concerns as to the extent of his/her involvement. As a final criticism, reviewers noted that the applicants failed to adequately discuss alternative routes for testing should the proposed animal models prove to be insufficient. In summary, reviewers felt that this effort represented an excellent concept, was of solid rationale, and could have a potentially high impact in the field of regenerative medicine. While much of the preliminary work was encouraging, it was not clear that resulting candidates would be viable in the clinic. Furthermore, the proposed preclinical validation studies were inadequately described. Finally, despite a strong multidisciplinary collaboration, reviewers were uncertain whether the project could be effectively managed.