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CIRM MAJOR FACILITIES GRANT APPLICATION #FA1-00608-1

Recommendation: Not recommended for further consideration
Element X Score: N/A
Element Y Score: —
Element Z Score: N/A
Use & Contribution Score:—

Public Abstract (provided by applicant)

The Stem Cell Unit will focus on host-pathogen interactions at the level of the stem cell. At present, this is an understudied but critical area. We must have viral gene delivery systems that are safe and effective in stem cells. We must be able to determine if viral infection (for gene delivery) affects stem cell properties including proliferation, differentiation, homing, and engraftment. For instance, quiescent hematopoietic stem cells are highly resistant to infection by some bacteria and viruses, but are very sensitive to others. In most cases it is unknown whether infected stem cells will be able to function normally in the host. Most humans are colonized with multiple long-lived viruses in addition to a variety of bacteria that could become reactivated and infect transplanted stem cells. It is important to understand the ability of infected stem cells to transmit the infection to immune sanctuaries such as the brain. Even in the absence of direct infection of the stem cells, the presence of an ongoing host response to infection may modulate stem cell behavior. The investigators of Stem Cell Unit will address these important questions in cell-based and animal models. Our institution has an outstanding team of microbiologists addressing host-pathogen interactions in stem cells and other tissues, and who are developing new viral vectors for gene therapy that will effectively target stem cells. One of the leading investigators in cardiac stem cell therapy is piloting a novel therapeutic approach to cardiac repair. Another team has established a sensitive animal model to detect the role of stem cells in normal cell turnover in the heart. Using this model they are poised to determine if ‘benign’ childhood infections reduce the number of stem cells in the heart, resulting heart failure later in life. Our institution is the largest source of trained workers for the vibrant biotechnology industry in the region. Training with faculty engaged in stem cell research is the primary modality by which students gain this important expertise. The Stem Cell Unit will provide a state-of-the-art research environment including space for much-needed core facilities. It will create a desirable environment for potential faculty recruits, allowing us to build a stronger academic program at our institution. The discoveries made in the Stem Cell Unit may lead to new tools for gene therapy, better methods for stem cell therapy, and a detailed understanding of how the presence of infection may affect the success of stem cell therapy in patients. Research in the Stem Cell Unit, which is focused on the effects of infection and inflammation on stem cell function, will lead to new insights in stem cell biology and human disease.

Statement of Benefit to California (provided by applicant)

The Stem Cell Unit will focus on host-pathogen interactions at the level of the stem cell. At present, this is an understudied but critical area. We must have viral gene delivery systems that are safe and effective in stem cells. We must be able to determine if viral infection (for gene delivery) affects stem cell properties including proliferation, differentiation, homing, and engraftment. Most humans are colonized with multiple long-lived viruses in addition to a variety of bacteria. These formerly quiescent pathogens may become reactivated upon stem cell transplantation, and potentially could target the stem cells themselves. Since stem cells can be immune privileged, it is important to understand the ability of infected stem cells to perpetuate the infection and to carry it to immune sanctuaries such as the brain. Even in the absence of direct infection of the stem cells, the presence of an ongoing host response to infection may modulate stem cell behavior. The investigators of the Stem Cell Unit will address these important questions in cell-based and animal models. Our institution has an outstanding team of microbiologists addressing host-pathogen interactions in stem cells and other tissues, and who are developing new viral vectors for gene therapy that will effectively target stem cells. We have one of the leading investigators in cardiac stem cell therapy who is piloting a novel therapeutic approach to cardiac repair. Other cardiac investigators have established a sensitive physiologic model to detect the role of stem cells in normal cell turnover in the heart, and are poised to determine if ‘benign’ childhood infections limit stem cell reserve, with resulting cardiac dysfunction later in life. Our institution is the largest source of trained workers for the vibrant biotechnology industry in the region. Expertise in stem cell methodology will become increasingly important. Training with faculty engaged in research is the primary modality by which students gain this experience. The Stem Cell Unit will provide a state-of-the-art research environment including space for much-needed core facilities. The availability of construction funds will enable us to allocate other resources towards the purchase of the sophisticated equipment that will be required. It will create a desirable environment for potential faculty recruits, allowing us to build a stronger academic program at our institution. The citizens of California will benefit from the discoveries made in the Stem Cell Unit, and the students that graduate from our institution will be better equipped to make productive contributions to the growing biotechnology industry of our state, thereby ensuring that California continues to lead the field.

Review Report

Executive Summary

This proposal is from an institution with a new and developing program. Its unique emphasis is to determine the effect of infectious disease agents and associated host responses on stem cell survival, proliferation and engraftment. The applicant institution is not a powerhouse for research, but they have built on existing strengths in the microbial basis of chronic diseases (increasingly recognized for its importance in common clinical problems) to develop a stem cell program in the effects of infection and inflammation on stem cell fate. The proposal is well-written and presents a combined approach to the role of infection and inflammation in stem cell biology, particularly cardiac stem cells. The detailed descriptions of the facilities are sufficient to see that the plans are well-thought out and individualized to the needs of the core investigators. The feasibility of the proposed work is high, appropriately focused and limited in scale, and importantly, clinically-driven.

A unique aspect of the proposal is the applicant’s claim of the importance of this institution for training undergraduates and graduate students in stem cell methodology to fill the ranks of technicians needed for academic and commercial growth in California in the area of stem cell biology. It is clear from the proposal that the small faculty group is interactive scientifically, and the focus of the stem cell unit is clear (i.e., it has focus, unlike the larger centers that can afford to be diverse). The applicants propose weekly meetings for seminars and lab group meetings which is possible because of the small size of the group. Another strength is the surprising success of the faculty in intellectual property transfer for their research programs.

This institution seeks CIRM support for a building that is up and ready, but not yet fitted with equipment, and space for recruiting new stem cell investigators. The applicant’s consider their work to be entirely pre-clinical (this program is competing in the Y element only), and the proposal is enveloped in the context of real clinical problems. The facility would provide a state-of-the-art research environment specifically for research space and core facilities, including a human embryonic stem cell (hESC) culture facility. No consortium agreements with other institutions are included in the proposal, which is a concern since the programs outside the facility don’t quite fit into the overall organization of a stem cell program. The focus areas are directed at developing safe and effective viral gene delivery to stem cells, mechanisms of (developmentally-regulated) stem cell resistance to infection, effects of infection on homing and engraftment of stem cells, and the effect of host response to infection on stem cells.

The main weakness of the proposal stems from the organization being early in its development, making the projects risky, and the investigators do not provide enough preliminary data to support their hypotheses. Furthermore, the track record is not on par with other organizations, and it is not clear that the investigators have the required expertise in embryonic stem cells, specifically with respect to running a training program. While the scientific program is very focused and poses an interesting question, it is disjointed in its presentation as various aspects are not synthesized into a program that can be followed. Reviewers were supportive of this application as a research grant, as the clinical idea is good and important; however, the application is not appropriate for a full facilities grant.

Detailed Summary

Element Y

Score: —

SCIENTIFIC PROGRAMS: Research in the Preclinical Research Program will address major issues surrounding host-pathogen interactions at the level of pluripotent stem cells and their derivatives, development and optimization of viral-mediated gene delivery systems into stem cells, and the impact of such manipulations on stem cell properties. The impact of pathogens on stem cell behavior and of infected stem cells on the host long term will also be addressed. Preclinical research in the area of cardiac repair and the impact of childhood infections on cardiac stem cell reserve are already in progress. The research direction capitalizes on an established program of microbiologists studying host-pathogen interactions (with a focus on cardiac disease), existing strengths at the institution, and the potential for some areas to move toward preclinical development and clinical trials.

The stem cell group as a whole serves as a bridge between the heart institute and a center for microbial sciences, as clearly outlined in the proposal. The director of the center is interested in developing stem cell-based therapies for cardiac diseases caused by drug toxicity, while another investigator studies stem cell-mediated regeneration of damaged myocardium. The role of a specific factor in stem cells will also be studied in response to stress, as well as the ability of this factor to recruit bone marrow progenitor populations to ischemic areas of injury. Other research topics include identifying pathways for regeneration that have been lost or repressed during evolution, and studying viral infection of stem cells, such as understanding the mechanisms of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infection, or altering the exclusion of stem cells by the blood-brain barrier. The goal of this latter research is to develop new stem cell-based therapies for central nervous system (CNS) diseases.

While one reviewer felt that there was not much science described, another reviewer felt that the research overall is clinically compelling, and designed to fill gaps in knowledge needed to get stem cell therapies into the clinic. The applicants have cleverly picked areas where research is needed but that are not popular to investigate. The research proposal identifies clinically relevant areas of crossover between microbiology and translation of stem cell therapies.

FORMAL INSTITUTIONAL COLLABORATIONS: The investigators have picked very clinically-important issues, and obviously collaborate closely. The new facility would be available to resident faculty, with lab and office space dedicated to existing and visiting investigators. All local faculty will have access to facility core services. There is some evidence of collaboration among the resident PIs. The investigators will make the stem cell facility available to outside institutions. While it is clear that there is substantial interest in enhancing both institutional and external collaborations, the actual approach explaining how the development of this facility space will assist in such collaborations is missing. There was minimal inter-institutional collaboration. No description was provided documenting existing collaborative agreements with biotechnology companies or other institutions.

CORE SERVICES: The applicants propose a culture facility dedicated to hESC and other adult stem cells which is large considering the relative small scale of the overall operation. Four core services will be established in the new CIRM facility. Cores will include: 1) Biosaftey Level (BSL) 2/3 Cell Culture Core with flexible space for the BSL3 built into the design so that it does not have to be open at all times, 2) Cell Culture Core for unapproved hESC lines, 3) Cell Sorting Core, and 4) Animal Procedure and Imaging Core. They also propose a separate space for cultivation of infected stem cells, which is important given the focus of the science, and a small independent space is set aside for non-federal line research. The culture facility is planned to contain a fluorescence-activated cell sorting (FACS) machine, which has a large footprint. Another reason the core is relatively large probably has to do with its use as a training facility (education in stem cell isolation, cultivation and handling).

One full-time person will administer the core facilities, and the institution supports 25% of the person’s salary. Core facilities for the whole campus are available to the stem cell group, (but not in the new facility) including quarantined animal housing, autoclave, and procedure rooms (where CIRM funding is requested for renovations), a transgenic mouse core, and a microscopy and histology core. The description of the core is detailed and well thought-out, but the track record for managing cores, e.g. productivity and number of active interdisciplinary collaborations using cores, was not presented. How the institution manages intellectual property, technology transfer, etc also was not presented.

PLANS FOR GROWTH: It is clear that the applicants are committed to investing in stem cell research based on recent recruitments and the proposed support for new faculty, although the total amount is not clear and the proposed strategy of developing stem cell research was not explicitly discussed in the application. In addition to core space, space will be allocated to communal research work areas for non-NIH approved hESC work, with lab benches for investigators, students, and core facility staff. At present, no faculty have been assigned space. Expansion plans are to reinforce the current faculty with a small number of new recruits over the next 2-4 years. Overall in the building nearly ten new faculty are to be hired, and their areas are not designated, so funding for stem cell work could lead to new hires into multiple departments with some stem cell interest.

Use & Contribution

Score: —

The institution will provide research space for two faculty recruited in the next 2-4 years. This ‘NIH free’ space and communal equipment for non-approved cell lines will be made generally available. The applicant proposes to construct space for stem cell research for two individual investigators (labs and offices), administrative office space, shared NIH free bench space and core facilities and associated personnel office space. This is a very small facility with some shared resources, particularly a FACS machine and some imaging. Funds will be used to renovate the Vivarium, remodel a pathogen quarantine suite, remodel a microscopy core, and add an histology core. Modification of existing microscopy core and expanded vivarium space will enhance stem cell research at the institution. Importantly, funds also will be used to develop a BSL2/3 facility for working with infectious agents.

The proposed cores are appropriate and necessary for the work proposed; however, based on the facility and program descriptions, it is not clear that this is will be a well-organized, integrated group for moving discoveries through the translational pipeline ultimately to the clinic. A greater description of the institution’s vision for the stem cell program, future key strategic investments, and approach to clinical translation would have been helpful.

Programmatic Discussion

 

A motion was made to recommend that this application be removed from further funding consideration as a CIRM Special Program. Reviewers commented that the science in this proposal was unique and addressed clinically driven questions about infectious diseases which could be important. However, the scientific proposal is very speculative and limited in scope, and the panel felt that the projects weren’t strong enough to warrant building an entire facility around this science. Another panelist commented that an additional feature is that this application focused on the training of technical staff, and this could be a resource for others in the state, but panelists felt that the training of technical scientists could be better accomplished at other institutions with proven track record in stem cell biology. This application would be more feasible as a research grant, or perhaps for a training grant.

The following Working Group members had a conflict of interest with this application and were therefore recused from participating in review of, discussion of, and voting on the application:

• Feit, Marcy