$6 443 455
Stem cells offer tremendous potential to treat previously intractable diseases. The clinical translation of these therapies, however, presents unique challenges. One challenge is the absence of robust methods to monitor cell location and fate after delivery to the body. The delivery and biological distribution of stem cells over time can be much less predictable compared to conventional therapeutics, such as small-molecule therapeutic drugs. This basic fact can cause road blocks in the clinical translation, or in the regulatory path, which may cause delays in getting promising treatments into patients. My research aims to meet these challenges by developing new non-invasive cell tracking platforms for emerging stem cell therapies. Recent progress in magnetic resonance imaging (MRI) has demonstrated the feasibility of non-invasive monitoring of transplanted cells in patients. This project will build on these developments by creating next-generation cell tracking technologies with improved detectability and functionality. Additionally, I will provide leadership in the integration of non-invasive cell tracking into stem cell clinical trials. Specifically, this project will follow three parallel tracks. (1) The first track leverages molecular genetics to develop new nucleic acid-based MRI reporters. These reporters provide instructions to program a cell’s innate machinery so that they produce special proteins with magnetic properties that impart MRI contrast to cells, and allow the cells to be seen. My team will create neural stem cell lines with MRI reporters integrated into their genome so that those neural stem cell lines, and their daughter cells, can be tracked days and months after transfer into a patient. (2) The second track will develop methods to detect stem cell viability in vivo using perfluorocarbon-based biosensors that can measure a stem cell's intracellular oxygen level. This technology can potentially be used to measure stem cell engraftment success, to see if the new cells are joining up with the other cells where they are placed. (3) The third project involves investigating the role that the host’s inflammatory response plays in stem cell engraftment. These studies will employ novel perfluorocarbon imaging probes that enable MRI visualization and quantification of places in the body where inflammation is occurring. Overall, MRI cell tracking methods will be applied to new stem cell therapies for amyotrophic lateral sclerosis, spinal cord injury, and other disease states, in collaboration with CIRM-funded investigators.
Statement of Benefit to California:
California leads the nation in supporting stem cell research with the aim of finding cures for major diseases afflicting large segments of the state’s population. Significant resources are invested in the design of novel cellular therapeutic strategies and associated clinical trials. To accelerate the clinical translation of these potentially live saving therapies, many physicians need method to image the behavior and movement of cells non-invasively following transplant into patients. My research aims to meet these challenges by developing new cell tracking imaging platforms for emerging stem cell therapies. Recent progress in magnetic resonance imaging (MRI) has demonstrated the feasibility of non-invasive monitoring of transplanted cells in patients. This project will build on these developments by leading the integration of MRI cell tracking into stem cell clinical trials and by developing next-generation technologies with improved sensitivity and functionality. Initially, MRI cell tracking methods will be applied to new stem cell therapies for amyotrophic lateral sclerosis and spinal cord injury. In vivo MRI cell tracking can accelerate the process of deciding whether to continue at the preclinical and early clinical trial stages, and can facilitate smaller, less costly trials by enrolling smaller patient numbers. Imaging can potentially yield data about stem cell engraftment success. Moreover, MRI cell tracking can help improve safety profiling and can potentially lower regulatory barriers by verifying survival and location of transplanted cells. Overall, in vivo MRI cell tracking can help maximize the impact of the State’s investment in stem cell therapies by speeding-up clinical translation into patients. These endeavors are intrinsically collaborative and multidisciplinary. My project will create a new Stem Cell Imaging Center (SCIC) in California with a comprehensive set of ways to elucidate anatomical, functional, and molecular behavior of stem cells in model systems. The SCIC will provide scientific leadership to stem cell researchers and clinicians in the region, including a large number of CIRM-funded investigators who wish to bring state-of-the-art imaging into their clinical development programs. Importantly, the SCIC will focus intellectual talent on biological imaging for the state and the country. This project will help make MRI cell tracking more widespread clinically and position California to take a leadership role in driving this technology. An extensive infrastructure of MRI scanners already exist in California, and these advanced MRI methods would use this medical infrastructure better to advance stem cell therapies. Moreover, this project will lead to innovative new MRI tools and pharmaceutical imaging agents, thus providing economic benefits to California via the formation of new commercial products, industrial enterprises, and jobs.
The candidate principal investigator (PI) is a relatively early career academic scientist with an active research lab and a demonstrated leadership role in directing core facilities for medical imaging. The PI’s focus has been on developing new magnetic resonance imaging (MRI) methods and tools to visualize cellular and molecular processes, and to track cells in tissue with increasing sensitivity. The candidate is a founder, board member, and scientific advisor for a biotechnology company that was created to further develop and commercialize his/her inventions. The PI’s research proposal focuses on the development of new tools to monitor cell location, fate and survival after delivery into the body, major challenges in the path toward clinical translation of stem cell-derived therapeutics. The applicant plans to develop new, non-invasive cell tracking methods for MRI and to collaborate with CIRM-funded investigators to incorporate these new methods into preclinical and clinical studies of neural stem cells for amyotrophic lateral sclerosis (ALS), spinal cord injury and other disease states. The sponsoring institution has recently built a comprehensive, multi-modal molecular imaging core facility for which the candidate will provide scientific direction and oversight. The institution will provide a full-time faculty position, matching funding and dedicated blocks of effort and equipment usage in the imaging core to support the PI’s research on this award. Research Vision and Plans - Reviewers described the PI’s research as highly innovative, focused on a very important area that spans across all applications of stem cell regenerative medicine, and potentially transformative for researchers in California. - Reviewers were enthusiastic about the PI’s plans to train new users on state-of-the-art equipment and methods and to collaborate with researchers to facilitate progress on stem cell-based projects already under CIRM-funded development. - While reviewers expressed interest in the research projects proposed by the applicant, there was some disagreement about whether improvements in MRI technology were needed to advance the clinical translation of stem cell-based therapeutics. PI Accomplishments and Potential - The applicant is viewed as an authority in development of MRI reporters and as an emerging leader in stem cell research. His/her work is viewed as highly innovative and widely applicable, as evidenced by publications and collaborations in a number of disciplines, including physics, developmental biology, neuroscience, immunology and clinical translation. - Previous inventions by the PI have become widely used in the MRI field. Additional work proposed by the PI to develop tools for analysis of cells at a single-cell level was viewed as likely to advance the field significantly. - The PI has successfully established an independent research program and concurrently directs an imaging service core facility. - The PI has published extensively, has received considerable press coverage for his/her inventions and innovations, and is invited frequently as a seminar presenter (both nationally and internationally). While some reviewers noted there were relatively few publications in the highest profile journals, others commented that the publication record was appropriate for a leader in the development of new MRI technologies and tools. It was also noted that the PI is an inventor on 8 patents, which is an uncommon accomplishment for an academic scientist. - While the PI has received funding from the National Institutes of Health (NIH) and industry grants, and is the Project Leader on an active NIH Program Project Center Grant, some reviewers expressed concern that much of the PI’s funding was ending soon and/or up for renewal. - Reviewers commented that the letters of support for the PI were strong, but some expected inclusion of letters from a broader range of individuals. Institutional Commitment and Environment - The PI would join an active regenerative medicine group that has a focus on imaging stem cells and would assume strategic leadership of an existing imaging core facility. Reviewers predicted that both the PI and the team would be strengthened by the collaborative environment, with resulting progress in cell tracking capabilities made across multiple platforms. - The molecular imaging facilities, which the PI would direct, and have dedicated access to, have been recently completed and provide modern research equipment and extensive infrastructure for preclinical and clinical applications. The PI would have access to multiple core facilities for nuclear magnetic resonance (NMR), pluripotent stem cell culture and preclinical research. In addition, the institution has provided adequate office and laboratory space. - It was not clear from the application if the institution’s offer included the purchase and relocation of the PI’s current MRI equipment. - Some reviewers judged the startup package and commitment provided by the institution to be adequate but not overly impressive.
- A motion was made to move this application into Tier 1, Recommended for Funding. Discussion centered favorably on the additive value that the PI would bring to the existing regenerative medicine group at the sponsoring institution. There was some disagreement among the panelists regarding the potential impact of the PI’s research proposal; while some felt it exemplified a series of leading-edge, possibly transformative approaches to a critical translational bottleneck (imaging stem cell-based therapies), others felt that improved MRI technologies were not a critical near-term need for the field. The motion carried.