Tools and Technologies I
One of the great promises of stem cell research is that doctors will find a way to isolate and modify patient’s stem cells so that they be reinjected into patients to treat their disease. Current examples include islet cell transplantation to treat diabetes, stem cells for treating heart failure, or engineered immune cells for treating cancer. However, a key challenge is to be able to monitor the cells after they have been administered. Scientists need to be able to follow the transplanted cells, to see if they survive and engraft, home to areas of disease, and whether they are able to reestablish the activity needed to counteract disease. We are developing novel tools to follow the fate and function of transplanted stem cells, based on a powerful medical camera called the PET scanner. PET imaging, or positron emission tomography, allows doctors to visualize the biology of cells in living organisms, including patients. Three ways to follow transplanted cells are being developed. In one, distinctive changes of functions inside cells will be probed using radioactive small molecules. In a second approach, antibodies will be used to detect cells based on distinctive markers on the surface of the transplanted cells. In the third approach, the transplanted cells themselves will be “marked” using genes that will cause the cells to emit a signal detectable by the PET scanner. Our interdisciplinary team has already demonstrated examples of these approaches and how they can be implemented in the clinic. Tools for watching transplanted cells will provide highly valuable information that will refine research, accelerate development, and most importantly, allow physicians to directly monitor their activity and effects in patients.
Statement of Benefit to California:
California has asserted a lead position in stem cell research and development of cell-based therapeutics. However, we currently lack good methods to follow transplanted cells once they are infused back into the patient, and knowledge about the survival, homing, and therapeutic activity of these cells will be critical for developing effective treatments. California has also led innovation in the field of molecular imaging, which can provide precisely the tools needed to monitor and evaluate cell based therapies. This proposal provides a unique opportunity to capitalize on the innovations of the California molecular imaging community, and to focus it on the specific needs of the stem cell community. The potential synergies generated locally and within the state will serve to accelerate overall progress and stands to benefit Californians first.
This proposal aims to develop a wide diversity of novel probes for positron emission tomography (PET) imaging that allow for in vivo imaging of cell-based therapies in regenerative medicine and oncology that are translatable from animal models to patients. The technology development focuses on three themes that involve the design of small molecule PET probes, antibody-based PET probes, and novel reporter genes optimized for clinical monitoring of transplanted cells. The ability to track the distribution, engraftment, and proliferation of transplanted stem cell-derived populations is of considerable importance in the field and thus reviewers agreed that the potential impact of this proposal is significant. The design strategy was considered well conceived and each aim allows for clinical research studies. The PI has assembled a remarkable and large team in order to deliver milestones within a 2-year period. Overall, reviewers thought that the proposed milestones are logical and well described. The PI has assembled a large team and the preliminary data suggest that all aims can be completed. One reviewer felt that the principal drawback to this proposal is the need to more fully address potential pitfalls specifically related to use of the probes in stem cell populations, and use of the stem cells in immune-competent recipients. Most of the studies outlined in the proposal are focused on tracking immune T cell populations in hosts that may be immunocompromised. The immediate and direct applicability of this technology to embryonic stem cells or iPS cells, for example, was unclear since specific studies addressing translation of the technology to stem cell populations were not proposed. Reviewers were nevertheless excited about the development of this technology that if applied to stem cells would be valuable. Reviewers felt that the PI is very accomplished and well qualified for this project and has assembled a strong team. The PI also has outstanding support and equipment. The team has a proven track record with high likelihood of being able to accomplish the stated objectives. The ability to effectively track transplanted cell populations in vivo is a key issue that needs to be addressed to move cell therapies forward. Although this proposal utilizes hematopoietic cells as the primary subject for developing the probe technology, reviewers felt that the strengths in research design, approach, and PI’s experience would lead to a valuable and broadly applicable set of tools for stem cell research.