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CIRM MAJOR FACILITIES GRANT APPLICATION #FA1-00612-1
Recommendation: Recommended for further consideration as a CIRM Institute
Element X Score: 94
Element Y Score: 94
Element Z Score: 90
Use & Contribution Score: 92
Public Abstract (provided by applicant)
The Stem Cell Research Program will build upon a long history of achievement in regeneration and developmental biology. Program scientists have made key contributions to developing stem cells, understanding how and why cells are lost in aging, understanding how tissues regenerate, and developing methods to make high purity cells from human embryonic stem (hES) cells for treating diseased or damaged tissue. The program consists of basic scientists carrying out research to elucidate the fundamentals of stem cells; translational scientists testing the feasibility of moving basic studies to the clinic; and clinical scientists who study specific diseases and afflicted patients. The new CIRM Institute will help spawn a new paradigm in medicine, namely interdisciplinary disease-focused teams consisting of basic, translational and clinical scientists. Disease-focused teams will guide discoveries from the lab bench to the bedside. The program will focus on neuromotor disorders such as those caused by spinal cord injury, multiple sclerosis, and stroke; neurodegenerative disorders such as ALS (Lou Gerhrig’s disease) and retinal degeneration, and metabolic disorders, especially diabetes. In these areas, stem cell basic research has led to preclinical testing, involvement with biotech companies, and progress towards clinical trials. Refining pipelines for stem cell therapies has been our focus for several years and the Institute will significantly facilitate our ability to move treatments through all phases of development with human therapies as the end goal. Importantly, the Institute will provide federal-funding-free space and core resources to facilitate integration of all phases of the process, from studies of basic stem cell biology, especially hES cells, preclinical testing and clinical trial design. As the hub of our stem cell program, the building design, with its shared open labs, clinic space, distributed interactive spaces, and conference rooms, supports both formal and informal research collaborations and dialogue. Patients will be examined in the building, where all phases of stem cell research intersect. Importantly, the building will provide the space for a major new recruitment of the best and brightest minds, that will allow the stem cell research program to flourish over the next ten years. In addition, the Institute will facilitate the development of new research tools, and the design of stem cell clinical trials with meaningful results, by integrating human performance based measures to identify the most appropriate population for first efficacy-in-humans trials and outcome measures. These tools will be regional and statewide resources. Critically, the new building will allow expansion and improvement of this pipeline by providing the critical resources, space, collegial expertise, and multidisciplinary interactions necessary to move basic research to preclinical models to human therapies, and provide broad education and outreach.
Statement of Benefit to California (provided by applicant)
A primary goal of Proposition 71 is to translate basic stem cell research to clinical applications. The disability and loss of earning power and personal freedom resulting from a disease or disorder are devastating and create a financial burden for California in addition to the suffering caused to patients and their families. Therapies using human embryonic stem cells (hES cells) have the potential to change millions of lives. Using hES cells as models of disease will help us understand the underlying causes of disease and likely aid in the development of drugs to treat those diseases. For the potential of hES cells to be realized, California researchers need the equipment, lab space, and personnel to develop hES cells into viable treatments. Federal constraints on hES cells create a critical need for buildings equipped and staffed with non-federal funds. The raison d’etre for the proposed building is to provide a single unifying facility to serve as a nexus for stem cell research on campus and regionally, that will enable expansion of the stem cell research program, house six new faculty recruits, stimulate and provide space for new interdisciplinary research, and provide a home for training and outreach activities. The breadth and depth of the stem cell biology and regenerative medicine research program, which has already made important advances and secured significant funding from CIRM, will act as a catalyst for new fundamental discoveries in stem cell biology, which in turn will germinate the process of development of translational research, leading to new treatments for human disease and disorders. Anticipated benefits of our Program and building to the Citizens of California include:
1. Creation of an Institute that will attract the best and brightest minds to the state 2. Development of new cell-based treatments for a variety of diseases and disorders 3. Generation of new techniques for using stem cells (and derived cells) to deliver drugs or other agents to tissues, thereby developing new treatment methods 4. Improved methods for understanding normal development and environmental risks to the early embryo 5. Improved methods for detecting and understanding effects of toxicants in the environment and workplace 6. Improved clinical trial methodology that will directly impact human testing of stem cell therapies 7. Development of new improved methods for developing and testing drugs for treating disease 8. Transfer of new technologies and intellectual property to the public realm with resulting IP revenues coming into the state 9. Creation of new biotechnology spin-off companies based on generated intellectual property 10. Creating interdisciplinary research teams that will have a competitive edge for obtaining funding from out of state 11. Creation of new jobs in the biotechnology sector.
It is anticipated that the return to the State in terms of revenue, health benefits for its Citizens and job creation will be great.
Review Report
Executive Summary
This is an outstanding application for one of the strongest stem cell centers in California. This proposal for transitioning from basic to clinical work is well written and exercises clear grantsmanship, and involves very strong faculty with a strong track record. The institution has a large number of CIRM investigators, superb core facilities, and very extensive collaborations. It is an ideal atmosphere for a stem cell scientist who wishes to collaborate with the best in the field.
This program is competing in all three elements from basic to clinical research. The new CIRM facility will serve as the hub of stem cell research, housing new scientists, new core facilities, and teaching and outreach activities as well as space for a patient advocacy committee and community-based fundraising. The new CIRM facility is proposed to integrate all stem cell research at the institution and thus facilitate and encourage collaboration. The plan is to use the facility to develop interdisciplinary disease-specific teams, both intellectually and physically, bringing together basic, preclinical and clinical members. The proposed facility will provide physical proximity of investigators to one another and to core facilities. New investigators will benefit from proximity to established investigators, and the new space will allow outside faculty and investigators from other fields, disciplines and programs to occupy space and have access to core facilities. The presence of a regulatory core as a resource will also link the members of the teams.
Overall this program includes over 30 primary investigators holding 12 CIRM and 90 NIH grants. Fifteen investigators will be housed in the new facility including six new recruits. Throughout the application, it is unclear precisely which Principal Investigators (PIs) would be moving into the new facility, and which portions of the research described in the application would be conducted in the new building. Nevertheless, many faculty appear to be well funded and published in high impact journals and overall the scientific program appears excellent. The scientific program emphasizes areas of current strengths at the applicant institution. This includes for Element X basic biology of stem cells, specification into neuronal and endoderm lineages and the role of mitochondria in stem cell function. The applicant institution has a long-track record in Developmental Biology (30 years of NIH funding) and has established interdisciplinary teams focused on the areas mentioned above.
The program also has the potential for rapid clinical translation. Element Y comprises participants from 15 disease and disorder areas with stated strengths in neuromotor dysfunction, neurodegenerative disorders and metabolic dysfunctions, that were included due to their progress towards clinical applications. The Element Z program will develop clinical trials based on science from the previously described research programs and the examination and refinement of clinical trial methodology. Thus the focus of trials will be on neuromuscular/neurodegenerative and metabolic disorders. The applicant institution has significant experience with clinical trials, device and experimental drug testing. Overall, since 2000 the institution has filed > 400 INDs and 28 IDEs. While the scientific program is quite strong, the description of how the new facility will be managed to provide the highest level of facilitation, coordination and collaboration around stem cell research is less well-described. A number of new cores to be located in the new facility are described, and one weakness of the proposal is that there is no description of how these cores will be managed. However, the institution has a strong track record of operating such core services successfully.
Detailed Summary
Element X
Score: 94
SCIENTIFIC PROGRAM: Research in Element X will have three major foci: 1) basic biology of the pluripotent stem cell, 2) molecular mechanisms controlling differentiation specifically of cells to the neuronal and endodermal lineages, and 3) the role of mitochondrial function in both these areas. Fields were chosen because of existing strengths at the institution and the potential to move towards preclinical research. For instance, several CIRM-funded groups are examining pathways that regulate survival, proliferation, and self-renewal of human embryonic stem cells (hESC) using conventional and high-throughput screening and genetic modification.
Over 20 faculty are associated with Element X; the group is well-funded with 74 NIH and 11 CIRM grants since 2000, and has a very good publication record. In total, the proposal shows only three investigators to be located in the new facility, while at capacity the facility would house seven Element X faculty. The scientific program within the facility will include research in all three above-mentioned areas. One laboratory is also examining safety issues on non-human primates and genetic manipulation of ES cells. Senior faculty will foster team building between new recruits and clinicians, and proximity to core and training facilities as well as shared equipment will foster interactions and development of teams. This is an experienced, highly qualified group of investigators, and their research programs are judged outstanding.
The building will house the CIRM-funded Shared Research Laboratory and Training Course and has meeting spaces and open laboratories for use by those not located in the building. There is no description of how this space will be managed for these purposes, other than organizing the Element X Research Program around key senior researchers. In addition, there is no description of more formalized activities to facilitate interactions beyond physical proximity. A number of interdisciplinary and collaborative programs are mentioned, including molecular and mitochondrial medicine and genetics, a school of engineering and integrated nanotechnology, and a center for studying complex biological systems. The benefit of the new facility is ascribed to providing ‘services and research support’. Thus, while the scientific program appears quite strong, the description of how the new facility will be managed to provide the highest level of facilitation, coordination and collaboration around stem cell research is not well-described. Nevertheless, the institution has an established track record for moving basic research to early translational and preclinical research, and while the applicants could have described a stronger connection between elements X and Y, they will likely be successful based on their comprehensive plan and their record of building interdisciplinary teams.
FORMAL INSTITUTIONAL COLLABORATIONS: The institution has many formal collaborative agreements with other universities, and many sponsored collaborative agreements with biotechnology companies. A letter of support is provided regarding an established consortium involving researchers from the applicant institution and 12 partner institutions. Based on descriptions in Element Y, it would appear that most collaborations have been in Preclinical/Translational Research rather than in Basic and Discovery Research.
The new CIRM facility will have lab and office space dedicated to visiting investigators who will have access to facility core services. This is a very interesting concept, and while it is clear that there is substantial interest in enhancing both institutional and external collaborations, the actual approach for developing this facility space to assist in such collaborations is missing. For example, how will lab and office space for visiting faculty by allocated? Will investigators be solicited in specific research areas relevant to the two major themes in the facility? Will space be allocated for limited time?
CORE SERVICES: Five core services will be established in the new CIRM facility; each of these cores already exists, but will either be moved to the new facility or expanded to the new facility. Cores scheduled to be relocated to the new building include: i) Transfection Core for high efficiency transduction of hESCs; ii) Cytometry Core for high speed sorting and analysis; iii) High Throughput Small Molecule Screening Core; iv) Imaging Core, including 2-photon confocal and TEM; v) a Videoteleconferencing facility to enhance collaborations with other institutions. The planned core services are appropriate and the track record of management, operation and maintenance is excellent. However, there is little description of how these specific cores will be managed, where resources come from to run the cores and whether a charge-back system will be required for ongoing usage. For example, the application states that the Cytometry Core will be used to develop transplantable cell populations, yet this seems unlikely since these machines are not likely to be managed in a clinical-grade GMP compliant fashion. The applicant institution does have many existing cores, such as a genomics and bioinfomatics institute, a proteomics core, a transgenic facility, and a nanosystems research facility, and their long and excellent track record of managing cores effectively is supported by the productivity and number of active interdisciplinary collaborations. An office for technology alliances retains dedicated full time staff for stem cell related ventures.
PLANS FOR GROWTH: The stem cell research program has been designated as a Program of Excellence by the institution. It is clear that the institution is highly committed to investing in stem cell research based on this designation and their commitment of substantial financial support for new faculty. This includes support for six new faculty in centers for stem cell research, developmental biology and cancer. Four of these faculty will be associated with Element X, and all will be housed in the new CIRM facility. The proposed strategy of developing disease-specific teams, housing new recruits with experienced senior leaders in the field and focusing recruitments in specific areas (stem cell niche, nuclear reprogramming, etc) are well founded, and the commitment of new funds/positions is a strength of this proposal.
DISCUSSION: Reviewers agreed that this proposal contains an extremely strong set of faculty, and demonstrates clear institutional commitment. Appropriate cores are all present, and accessible to all. Reviewers liked the disease team concept, as well as the concept for visiting office space. However, the proposal does not describe a management plan for the space, or other formalized activities for how the facility will be used.
Element Y
Score: 94
SCIENTIFIC PROGRAM: The proposal for Element Y is beautifully thought out, and presents a wonderful model for how to think about translational research efforts. Moreover, the quality of the preclinical research is excellent. The program will seek to address challenges that impede moving basic studies into clinical applications. These include how to produce and separate specialized cells from ES cells, how to transplant such cells for different diseases, how to image transplanted cells, how to deal with immune rejection and to how to analyze outcomes. A key strength of this application is the formalized, institution-wide commitment to translational research. The proposal states that researchers, clinical staff and regulatory participants will be brought together in the new building.
The applicant institution has participants investigating 15 diseases and disorders with particular strengths in neuromotor/neurodegenerative and metabolic disorders. This is an experienced, highly qualified group of investigators with a substantial track record in relevant areas and a substantial number of grants and patents related to translational work. These investigators have already made seminal discoveries with hESCs, marrow stromal cells, mesenchymal stem cells (MSC) and adult neural stem cells (NSC) and advanced state of the art animal models with anatomical and behavioral outcome measures that assess safety and potential efficacy.
In the area of neuromotor dysfunction, several spinal cord projects involving different sources of stem cells are examining preclinical models in mouse and rat. An hESC trial is already planned. The institution has preclinical programs underway in multiple sclerosis, in stroke, and in the area of neurodegenerative diseases. The institution also has a mature Amyotrophic Lateral Sclerosis (ALS) /Spinal Muscular Atrophy (SMA) collaboration using hESCs as starting materials. In the area of retinal disorders several programs are in the preclinical phase, and one of these programs will take place in the new facility. The grant application anticipates discussion of stem cell-derived therapies with the FDA in the next few years. In the general area of metabolic diseases, several diabetes research programs are in preclinical development. These include new approaches to suppressing autoimmunity, and islet cell replacement approaches using hESCs and MSCs. Additional studies focus on mitochondrial contributions to metabolic syndrome and type 2 diabetes.
These programs will benefit from the organization of the new facility into disease-specific teams, and the proximity of shared resources. The preclinical program will be located near the clinical space and the Regulatory Core and Stem Cell Vivarium, which appear to be proposed to be located in the new facility.
A number of investigators working in the preclinical program will not be located in the new facility, but will take advantage of meeting space, open lab benches and training facilities in this space. The application describes interactions and collaborations of the preclinical program with several other units within the home institution. These include a spinal cord injury research center, an institute for brain aging, and a functional imaging center. The proposal mentions Center-wide town style meetings to discuss projects holding promise for human testing.
FORMAL INSTITUTIONAL COLLABORATIONS: In addition to several collaborative agreements with biotechnology companies, the applicants have a formal relationship with a nearby university that apparently has expertise and CIRM funding for studies on ES cell survival and differentiation through chemical genomics and non-coding RNA. The two institutions share a training program in stem cell techniques. A recent expansion of this course is funded by a CIRM grant, and this course will be housed in the new stem cell facility. The applicant institution also has an international collaborative agreement focusing on the use of hESC-derived neuronal progenitor cells in treatment of spinal cord injury in a clinically relevant model. Finally, one investigator has a collaborative agreement to obtain donated blastocyts and oocytes from a fertility clinic that has yielded several new ESC lines.
CORE SERVICES: Two core services related to Element Y will be established in the new CIRM facility: i) a Large Capacity Cell Culture Core that includes a proprietary cell culture system allowing large numbers of cells to be grown in a standard single incubator; ii) the Stem Cell Regulatory Core providing dedicated stem cell oversight of regulatory issues and guidance on hSCRO, IRB, FDA, IACUC and technology transfer issues. This office will apparently coordinate with existing regulatory and contracting offices at the applicant institution. Thus, this office appears to be very specialized with respect to stem cell matters. The cores are managed by a Masters-level person on a day-to-day basis with appropriate oversight.
Multiple other stem cell-related cores not being housed in the stem cell building are listed, and available for use by investigators, including: 1) Vivarium, 2) Transgenic Facility, 3) Human Stem Cell Genetics Core, and 4) Immune Tolerance Core.
PLANS FOR GROWTH: It is clear that the applicant institution is highly committed to investing in stem cell research based on the established support for six new faculty, two of whom will be recruited for Element Y and will be housed in the new facility. The proposed strategy of developing disease specific teams, housing new recruits with experienced senior leaders in the field, and focusing recruitments in specific areas are well founded.
DISCUSSION: Reviewers were very impressed with Element Y of this proposal because the applicant’s track record clearly indicates that they have already been successful in translational efforts. The application discussed the need to have regulatory services available very early on to translate these findings to clinic, which is important. Moreover, a formalized infrastructure already exists for teams of clinical, regulatory and other personnel. A minor weakness was reiterated by one reviewer who wanted to know how the space will be used operationally.
Element Z
Score: 90
SCIENTIFIC PROGRAM: The applicants have significant experience with clinical trials, device and experimental drug testing. Overall, the institution claims > 250 active clinical trials, and > 400 INDs and 28 IDEs since 2000. Four primary investigators will be moving to the new facility in this Element. Potential clinical trials will benefit from a robust regulatory infrastructure and the formalized, institute-wide translational research program that will guide FDA-compliance in all phases of preclinical and clinical research. A major goal of the Element Z Program is the examination and refinement of clinical trial methodology, including choice of entry criteria and use of surrogate endpoints. The initial focus will be on the treatment of spinal cord injury and retinal disorders as these are the furthest in the preclinical development pipeline.
The proposed clinical research programs include a Neuromotor/Neurodegenerative Disorders program with a planned trial in spinal cord injury; human clinical trials are planned to test the potential of differentiated derivatives of hESC in ALS and SMA. Many previous trials focusing on retinal degeneration have occurred at the applicant institution. Consequently, there are several preclinical studies focusing on retinal treatments utilizing hESCs in development to treat age-related macular degeneration and diseased retinas.
The metabolic diseases program focuses in part on islet cell replacement therapies with projects seeking to develop insulin-producing cells from hESCs. Metabolic methods to prevent loss of cells after engraftment and strategies to prevent auto-immune destruction of islet cells also will be pursued. Non-invasive methods will be used to estimate pancreatic islet cell mass and track the function of transplanted cells during clinical trials. While robust, it is not clear which, if any, of these preclinical studies are near clinical trials.
Clinical researchers will have ‘significant space’ to see patients and perform clinical trials, including clinician offices, exam rooms, a treatment planning room, a neuromotor/gait laboratory, a core patient sample handling facility, storage and nursing support space. Based on the established track record of building interdisciplinary teams, the plan has a reasonable chance for success. However, increasing interactions with clinical faculty will be challenging because it appears that the majority of Element Z faculty will be located outside of the new facility. The application does not indicate how they will entice clinicians to the facility to integrate with the disease-specific basic and translational investigators, nor does the application specify how or who will manage this clinical space, or who will pay the costs of this space in an ongoing fashion.
FORMAL INSTITUTIONAL COLLABORATIONS: As with Element Y, the applicants have several collaborative agreements with biotechnology companies. Several examples of interdisciplinary intra-institutional interactions are also described, including interactions with a diabetes research center, a clinical spine injury program, a cancer center, and a stroke center. These collaborations are critical to the success of the Element Z Program because of their likely impact on patient recruitment and availability of investigators. In addition, the new facility will have lab and office space dedicated to visiting investigators who will have access to facility core services. There will be considerable clinical research outside the facility. However, the new facility will facilitate interdisciplinary collaborations by conferences and core services. Investigators will be brought together in ‘Town Hall’ like meetings, Stem Cell Grand Rounds and Stem Cell Seminars. The Regulatory Core also will guide interactions.
CORE SERVICES: For Element Z, the Human Performance Core service will be expanded in the new facility. This core will be used for neuroimaging, neurophysiology, cardiopulmonary testing, metabolic testing, skeletal muscle biology and robotic exercise physiology. A specific point of emphasis is to measure quality of life issues and quantitative behavioral changes. The new space will allow expansion of a transcranial magnetic stimulation laboratory, a gait analysis laboratory, and a room for eye exams. These resources are available to all stem cell researchers, but there is no description of how these services are funded and managed. Other core services that are available via the institution-wide translation research program include a Human Functional Imaging Core, and a Neuroimaging Core.
PLANS FOR GROWTH: No specific plans for faculty recruitments related to this program or addition of future cores are outlined, except for the statement that as basic studies and preclinical studies progress, clinical investigators will be added. This is a weakness, since provision and development of individuals with clinical trials expertise is often a major limitation in the implementation of trials.
DISCUSSION: Based on the statistics (INDs, trials, etc.) the institution’s track record is hard to beat. However, some reviewers felt that the plan for clinical work was not clearly described. One reviewer commented that the application gives the impression that the work in Element Z is simple to do, and expressed a concern over not recognizing the possibility of setting the field back by a great amount if a potentially premature trial goes awry. A discussant countered that the institute proposes a very strong regulatory component. Another reviewer is not sure why the application is so focused, and felt that the inclusion of clinician offices and clinical visit rooms doesn’t quite fit. Also, it is unclear why the human performance facility has to be on site. The quality of life emphasis is unique. A discussant also questioned whether immune rejection issues were considered as part of Element Z, and a reviewer responded that this is not addressed.
Use & Contribution
Score: 92
The new building will consolidate research activities with the goal of fully integrating related fields. The facility will not only become home to 6 new stem cell scientists, but will house the CIRM Training Program, Stem Cell Techniques Course, and the Stem Cell Emphasis Track of the institution’s Master’s Program in Biotechnology. The Stem Cell Core Facility that will be responsible for hESC derivations, cell culture, differentiation/purification and imaging devices also will be located in the building. Dedicated space will be set aside for regulatory staff for both preclinical and clinical studies. Further, outreach activities will have space to inform the public of activities, disseminate new discoveries and focus fundraising activities. The building will also provide temporary space for investigators and partners to perform pilot studies and space for corporate partners to test new technologies, and will have the capacity for worldwide teleconferencing.
The proposed facility will include utilize the design of a pre-existing building to accelerate the construction process. The proposed space allocation ratio is ~5: 2.5:1 for Element X : Element Y: Element Z. The proposed site is in the health sciences section of the campus ‘in the heart of biomedical research’ at the institution. Funds have been identified for six new faculty recruits and for building operations and maintenance, but there was not a specific management or business plan for the space. The building will accommodate 15 PIs with flexible unassigned space, although there was no specific plan for enhancing interactions other than the physical proximity of the researchers and the location of the cores.
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
- Sheehy, Jeff