In Utero Model to Assess the Fate of Transplanted Human Cells for Translational Research and Pediatric Therapies
Early Translational I
$4 214 592
Statement of Benefit to California:
The goal of this application is to establish an in utero preclinical model for monitoring the fate of transplanted cells, specifically hematopoietic precursors derived from umbilical cord blood or human embryonic stem cells (hESCs), with a long-term goal of treating inherited pediatric hematologic diseases. In the first aim, hematopoietic stem cells (HSCs) derived from cord blood and hESCs will be engrafted and the fate and distribution of the transplanted cells will be followed. For the second aim, a series of in vivo imaging methodologies will be employed to monitor the fate and migration of the engrafted cells. This proposal addresses several bottlenecks in clinical translation by: 1) addressing issues of hESC-derived cell optimization for clinical transplantation (e.g. expansion, safety); 2) providing insights into the fate and distribution of transplanted human cells in a preclinical model; and 3) conducting proof-of-principle studies for human transplantation in a relevant model. The reviewers agreed that the proposed effort represents a significant and interesting strategy for addressing several barriers to translation, particularly with regard to potential therapies for inherited pediatric diseases of the blood. Currently, there are few options for treating such disorders, and while cell therapies are thought to be promising, there remain many issues to resolve. One such obstacle is the threat of immune rejection, which the applicants have addressed by proposing a prenatal or early postnatal timing of cell administration. Due to the immaturity of the immune system at these stages, the threat of graft vs. host disease could be substantially reduced compared to current clinical scenarios. In addition, the reviewers appreciated the need for a preclinical model to address key safety and efficacy issues that must be resolved prior to testing in humans. In general, the reviewers were optimistic about the overall feasibility of this effort. The proposal was clear and well organized with realistic criteria for success. The research team was viewed as a considerable asset, comprised of successful and productive investigators covering complementary domains of expertise. Reviewers also noted as a strength the established model and imaging capabilities in the principal investigator’s (PI) laboratory. In addition to these qualifications, the reviewers discussed a number of strengths in the proposed experimental design. In particular, they appreciated the side-by-side comparisons for evaluating the fate of transplanted cell populations as well as the straightforward, bioluminescence imaging methodologies capable of detecting cell clusters. While their overall impressions were favorable, the reviewers expressed some concerns over specific aspects of this endeavor. The preliminary data were largely supportive. However, one reviewer commented that it was difficult to fully appreciate the preliminary data due to missing figure legends and an inadequate level of description. One reviewer questioned the feasibility of the positron emission tomography (PET) approach, as the proposed markers were not well described or supported by preliminary data. Even the citation provided for the PET methods did not reconcile the description provided by the applicants with the state of the art in the field. In addition to these minor points, the reviewers raised some questions about the immediate therapeutic potential of this work. Long-term engraftment and tolerance were discussed among the panelists as necessary preclinical translational milestones to assure life-long cure, and panelists were concerned that the proposal did not clearly address these issues. While noting that no diseases were specifically addressed, they recognized the utility of this model as a tool for development for a wide variety of disorders. They acknowledged, however, that similar studies using other models have been problematic, and wondered whether this particular preclinical system might be somewhat premature. Despite these reservations, most felt that potential benefits to be gained would outweigh the inherent risks. As a final point of discussion, several reviewers commented that the budget seemed excessive while others questioned whether the investigators might be overcommitted. In summary, the reviewers agreed that the proposed effort addressed several important barriers to translation. Overall, the experimental design was unique and feasible due to the strengths and experience of an outstanding research team. PROGRAMMATIC REVIEW During programmatic review, the Grants Working Group was instructed to consider the specific rank order of all applications in Tier I as an indicator of priority for funding. A motion was made to move this project below that of another with an identical score. The reviewers indicated that while in utero transplant models would be useful, studies similar to those proposed have been unproductive in other settings. Moreover, the overall immediate utility of this proposed project was less apparent than that of the project that achieved the same numerical score. The motion carried.