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CIRM MAJOR FACILITIES GRANT APPLICATION #FA1-00607-1

Recommendation: Recommended for further consideration as a CIRM Institute
Element X Score: 99
Element Y Score: 95
Element Z Score: 94
Use & Contribution Score: 93

Public Abstract (provided by applicant)

{REDACTED}is a nonprofit organization formed to marshal the intellectual resources of {REDACTED} world-leaders in life sciences research, including {REDACTED}. In addition to the collective strength of its members, {REDACTED} has established an extensive network of academic and industrial collaborators to efficiently and effectively expand the breadth and depth of its scientific, technological capabilities and resources. The {REDACTED} research program goals are, consistent with those of the California Institute for Regenerative Medicine (“CIRM”), to invent research tools and technologies to hasten the pace of stem cell research progress and to discover and develop diagnostics, therapies and cures to relieve human suffering from chronic disease and injury. The research interests of {REDACTED} member scientists are extraordinarily broad and deep and exceed what {REDACTED} can pursue in its initial resident basic research, preclinical research and preclinical development programs. That notwithstanding, resident and non-resident program will remain closely integrated by virtue of the strong scientific community and its demonstrably successful traditions of integrative collaboration. {REDACTED}’s basic research program is targeted to understand the fundamental biology of stem cells and pluripotency and consists of five research areas: Stem Cell Growth and Differentiation, Neuroscience, Cardiovascular Biology, Hematopoiesis, and Vision Science. {REDACTED}’s preclinical research program builds on the outcomes of its basic research program and includes investigations directed to the development of diagnostics and therapies. Preclinical research falls into seven major areas: Neurology, Cardiology, Hematology/Oncology, Endocrinology, Ophthalmology, Nephrology and Technology Development. The focus of the {REDACTED} preclinical development program is to move stem cell-based diagnostics and therapies into the clinic. {REDACTED}’s preclinical development and clinical research program emphasizes six major areas: Neurology, Cardiology, Hematology/Oncology, Endocrinology, Ophthalmology, and Technology Development. In addition {REDACTED} will launch a comprehensive outreach program intended to not only train the next generation of collaborative, multi-disciplinary scientists but also to engage the community in a dialogue about the ethics of research and endeavor to inform and educate the public about our scientific and medical progress and aspirations. By building only one new facility, by sharing space and expensive technologies and resources {REDACTED} represents an effective and efficient use of Proposition 71 funds and creates a synergistic research enterprise and community and statewide resource the whole of which is substantially greater than the sum of its parts.

Statement of Benefit to California (provided by applicant)

The premise of stem cell research is that we can harness the regenerative power of stem cells to understand, treat and cure degenerative diseases and injuries. The promise is that stem cells could offer the possibility of a renewable source of replacement cells and tissues to treat diseases including Parkinson’s and Alzheimer’s diseases, spinal cord injury, stroke, burns, heart disease, diabetes, osteoarthritis, and rheumatoid arthritis and that a better understanding of stem cells could help us to understand how diseases such as cancer and Alzheimer’s disease or how birth defects arise and suggest new strategies for therapy. {REDACTED} Investment in an {REDACTED} facility represents an exceptional, worthy investment by the California Institute for Regenerative Medicine. The {REDACTED} facility will provide ‘safe-harbor’ laboratories, free from Federal restrictions on stem cell research; will represent an efficient use of California resources by affording multiple organizations shared access to expensive technologies and space; and, will enable and facilitate multi-disciplinary, collaborative research. {REDACTED} is a historic alliance that marshals the intellectual resources of {REDACTED} world-leaders in life sciences research each of which has impressive complementary research strengths. By building only one new facility, by sharing space and expensive technologies and resources {REDACTED} represents an effective and efficient use of Proposition 71 funds and creates a synergistic research enterprise the whole of which is substantially greater than the sum of its parts. Collaboration is vital to hasten the pace of progress in science. As a result of the extraordinary growth in the body of scientific knowledge, life scientists have had to focus, to compromise breadth for depth of understanding of narrow, specific disciplines. Complex biological problems, however, raise questions that span disciplines. Development of solutions to complex problems requires that scientists collaborate. {REDACTED} is the only organization anywhere in the world created expressly to lower any and all barriers to inter-institutional and interdisciplinary collaboration among scientists. The {REDACTED} facility is intended to house biologists, chemists, technologists, bioengineers, computer scientists and clinicians in open laboratories and is designed to facilitate and encourage collaboration among them as required to translate the basic understanding of stem cell science into tools useful to diagnose and treat human disease. The facility will also serve as a hub of an extensive outreach program affording the community access to stem cell related resources and education opportunities.

Review Report

Executive Summary

The proposed CIRM Institute will be founded by four highly regarded local institutions. This is a powerful proposal competing in all three elements from basic to clinical research. The proposed research programs intend to expand our basic understanding of normal stem cell biology and capitalize upon this understanding to move new approaches to the clinic. The participants will pursue strategies to promote collaborations among biologists, clinicians, engineers, physicists, chemists, computer scientists, and ethicists in academia, the private sector, and government, to invent the next generation of tools for discovery, to train the next generation of stem cell scientists whose approach to solving medical problems is interdisciplinary, and to maximize community support and engagement by developing an informative outreach program.

The applicants worked with a laboratory planner to develop a space strategy. The plan is to build a new, innovative facility free from federal restriction on stem cell research in which 18 existing outstanding scientists, including 4 leaders in the field, will be housed in space that will feature open laboratories to facilitate collaboration. The proposed building will provide space for a total of 21 PIs, excellent core facilities including a vivarium, imaging and engineering facilities, bioinformatics, human stem cell training facilities, a patient cell bank, and educational/conference and outreach facilities. What they have not put into this site they have covered with impressive collaborations. Collaboration mechanisms include monthly meetings, weekly seminars and an annual symposium. They will recruit 10-15 Fellows directly from M.D., residency or Ph.D. training who wish to commit their careers to human stem cell research and therapy for human disease. Senior Scholars will draw leading scientists and experts on government policy/ethics to spend time in residence. Scholars also will participate in cooperative city-wide training activities such as “bench to bedside and back” as well as seminars on academic-private sector translation.

Over 100 investigators from four cooperating institutions will participate in the proposed program, and their productivity is represented by an impressive publication record in stem cell or relevant fields, by their patents and Investigational New Drug applications (INDs) and by their involvement in clinical trials. They are well-funded, including 24 investigators with 26 CIRM grants. The community has a long tradition of productive collaboration, which is reflected in the exemplary formal institutional collaborations described in the proposal.

The proposed five research areas for Element X include stem cell biology, cardiovascular disease, neurosciences, hematology/oncology, and ophthalmology, comprising critical and forward thinking experiments. Both Element Y and Z were considered to be very strong, as they provide a seamless transition to exceptional translational and clinical research; there are clear connections between Elements X, Y and Z. The member institutions have an established track record for moving basic research to early translational and preclinical research.

Detailed Summary

Element X

Score: 99

SCIENTIFIC PROGRAM: The quality of the investigators housed within the proposed program is outstanding. They represent a broad array of disciplines that are relevant to the ultimate goal of clinical interventions utilizing stem cell discoveries. There are over 50 primary faculty associated with Element X. Nine faculty including four CIRM-funded Principal Investigators (PIs) will be moving to the proposed CIRM facility. All of the major faculty are tenured and have high productivity, specifically in stem cell research, as reflected by publications and patents as well as NIH funding. Overall, the seniority and experience of the scientists to be housed in the proposed facility is impressive. Four very well-known senior investigators will relocate all or portions of their laboratories to the CIRM facility to anchor and lead the research programs. Their pivotal leadership will drive programmatic integration and their presence in residence will benefit mentoring of junior faculty, fellows and scholars. The synergies will be substantial. Proximity to core and training facilities and shared equipment will foster interactions and development of teams.

The scientific program to be housed in the CIRM-funded facility will include research in each of the five above-mentioned areas. The applicants present a compelling set of experiments that start with basic stem cell biology and move progressively to translation and the clinic. Reviewers praised many specific aspects of the proposed research programs, highlighting e.g. the basic stem cell biology program in which the PIs plan to characterize the in vitro and in vivo properties of stem cell lines derived from over 1000 cryopreserved normal and abnormal embryos. The reviewers felt that the proposed experiments are extremely energetic, forward thinking and critical and that the selection of cells to be used for interventions in human disease will be based on sound molecular and physiological rationale. Neuroscience is also a clear strength of the program’s many renowned leaders and similarly intriguing approaches for cardiovascular biology, hematopoiesis and ophthalmology are described. Taken together the applicants provide a clear roadmap of how the program will approach questions of the basic biology of stem cells in preparation for sequential translational steps. This is a powerful proposal in which the whole is greater than the sum of the individual parts which by themselves are of extremely high quality.

FORMAL INSTITUTIONAL COLLABORATIONS: This proposal manifests a model for formal institutional collaboration between the four participating institutions. Collaboration plans are described succinctly and will build on existing and complimentary work of many of the PIs in the local area which is known for its scientific leadership and excellence. Several formal institutional relationships have been established with additional institutions including a large Good Manufacturing Practice (GMP) facility, a supercomputer site at one of the member institutions, and several relevant institutes and industry leaders. One reviewer stated that s/he would not fault this element in any way.

CORE SERVICES: The Core services provided both within and external to the proposed facility are excellent and well suited to meet the demands of the participating laboratories. Three core services will be established in the new CIRM facility – an Education Core, Cyber-Infrastructure Core, and Microscopy Core. The Cyber-infrastructure core is truly innovative and recognizes the substantial need for analysis of massive data sets. It also will establish an optical fiber “data superhighway” to facilitate communication and data analysis as well as provide an HDTV telepresence for virtual teams to interact on short notice and at any time.

The new CIRM facility will house the existing intensive laboratory training course for CIRM trainees as well as the training program as part of the CIRM Shared Facilities grant. The participating institutions each have many existing cores, and are experienced in handling intellectual property and technology transfers.

PLANS FOR GROWTH: The plans for growth are described briefly, including the recruitment of new investigators in basic stem cell science and engineering at all levels of seniority for housing in the new CIRM facility as well as in the member institutions. The current planned growth areas are in stem cell growth and development, cardiac studies and Amyotrophic Lateral Sclerosis (ALS)-focused neuroscience, and mention is made of adapting to changing needs as the work proceeds and discoveries are made. While it is clear that the proposed program is highly committed to investing in stem cell research based on recent past, no proposal was presented for numbers of faculty to be recruited or financial investment for such recruitments over multiple years. No rationale was provided for the specific areas in which to recruit. Furthermore, it is unclear if part of the space vacated by investigators in their home institutions when moving to the new facility would be dedicated to stem cell research on the individual campuses.

DISCUSSION: The reviewers were overall extremely enthusiastic about this proposal, and the only criticism brought forth related to the plans for growth. It is unclear how and who the applicants will recruit, and it is uncertain whether the vacated space will be dedicated to stem cell research. This is especially important since the applicant institutions are land-locked. The reviewers lauded the proposed program as a model for collaboration, and felt that the participants are the who’s who of stem cell research of the four institutions assembled in one building.

Element Y

Score: 95

SCIENTIFIC PROGRAM: The participating institutions have an established track record for moving basic research to early translational and preclinical research. There are clear connections between Elements X and Y. Overall, there are over 30 primary faculty associated with the Preclinical Research Program. Seven PIs will be moving into the new CIRM facility, four are CIRM-funded. The research in each of the seven disciplines listed below will occur within and outside of the CIRM-funded facility. This is an experienced, highly qualified group of investigators with a substantial track record in relevant areas and a significant number of grants and patents related to translational work.

Research in the Preclinical Research Program will focus on seven principal areas: neurology, cardiology, hematology/oncology, endocrinology, ophthalmology, nephrology and technology development. Fields were chosen because of existing strengths at participating institutions and potential to move toward preclinical development and clinical trials. The Neurology program is exceptionally strong with pre-clinical animal models available for rescue with human embryonic stem cells (hESC), or by more differentiated cells, for several neurodegenerative diseases. These studies will foster interdisciplinary activity as they will need technologies, informatics, and computing beyond those typical of most stem cell biology laboratories. For example, high-capacity sequence analysis is required for hESC lines, and for cells taken from patients with clinical disease, to analyze what variants are present and which variants may contribute to cellular phenotypes. Furthermore, transplantation methods have been used extensively and in impressive, novel ways by these distinguished investigators. Important new technologies will be developed for improving cell delivery and for in vivo imaging. Innovative control measures are being developed to alleviate potential risks associated with cell-based therapy. A major collaborative initiative is focused on cell transplantation in ALS models and genomic analysis of sporadic ALS.

A major collaborative program in Cardiology, which is likewise exceptionally strong, will be housed in the CIRM facility. The program is focused on optimizing cardiomyocyte differentiation of hESC and developing novel methods for delivery of cells and drugs to damaged hearts and for their visualization.

Additional experiments are described for the other targeted research areas. Most are described in convincing detail to provide assurance that the work will lead to desired endpoints in transplantation. One reviewer felt that the Ophthalmology program lacks some detail. The Technology Development integrates very nicely with Element X and represents an added strength. The applicants will develop innovative nanotechnology and genotyping analyses to facilitate stem cell applications.

FORMAL INSTITUTIONAL COLLABORATIONS: The formal institutional collaborations are strong and represent meaningful contributions to the overall strength of the program. They are identical to those described in Element X. Although the collaborative agreements are documented, it was not clear to some reviewers how the CIRM facility scientists will integrate with the on-campus scientists. The meetings spelled out may not be adequate and will depend heavily upon cyber interactions.

CORE SERVICES: Core facilities both in the CIRM site and on campus are quite strong; they are appropriate and the track record of management, operation and maintenance is excellent. The core services to be established in the new CIRM facility include an Ethics Core, a Human Disease Cell Bank, a Large Scale Cell Culture Core, a Functional Genomics and Vector Development Core, and an Electrophysiology Core. Important additional cores exist at the participating institutions.

PLANS FOR GROWTH: The same limitations related to faculty recruiting as described for Element X hold true for Element Y. On the positive side, each member institution has made a strong commitment to stem cell research and has offered to adapt current and future space resources to the growth of the stem cell program. While it is recognized that future expansion may be difficult to predict, it would be helpful to offer a more concrete outline of specific areas to be strengthened.

DISCUSSION: The reviewers were very enthusiastic about Element Y. It is disease team-oriented and describes an excellent transition from basic to translational/clinical research. This is one of the stronger parts of this proposal. Specific program components were discussed as reviewers differed in their assessment of the proposed ophthalmology component. One reviewer thought it was strong, whereas another felt it lacked plans. The cardiology and nephrology components were highlighted for their excellence. The technology proposal was described as being really clever; the applicants are light-years ahead in the way they are thinking about delivery systems for cells.

Similar to their assessment of plans for growth in Element X, the reviewers felt that such plans are unclear for Element Y, but one reviewer expressed his/her trust that the applicant program will be successful at recruiting. The reviewers observed that the same investigators were pursuing Element X and Element Y research, which left some wondering if they can do it all, whereas others were convinced due to the caliber of the researchers involved that this was achievable, and that recruitment may fill the gaps. One reviewer considered the presence of the same scientists in Element X and Element Y to be a strength for moving basic research through to translational work.

Element Z

Score: 94

SCIENTIFIC PROGRAM: The investigators in Element Z both within and external to the program are outstanding – the science is innovative and their track record of stem cell discovery research, and cautious yet progressive approaches to the clinic, are impressive and in fact leading the field. Participating members are experienced in clinical trials. There are over 10 primary faculty associated with Element Z, with two PIs, one CIRM-funded, moving to the new CIRM facility. The member institutions have an established track record for moving basic research to early translational and preclinical research. There are clear connections between Elements X, Y and Z.

Element Z is a powerful program and will focus on treatment of neuro-degenerative diseases; cardiac disorders, including cardiomyopathy and congestive heart failure; hematological disorders; endocrinology, including transplantation of beta cells and beta cell progenitors; and ophthalmology. There is a strong commitment to technology development in stem cell tracking and detection in vivo, nanotechnology, and oocyte maturation in vitro, combined with oocyte preservation in their In Vitro Fertilization (IVF) facility.

The programs for neurodegenerative diseases are all well thought out based on extraordinary data, and one program has progressed to clinical trial consideration. Novel findings by members of the proposed program demonstrated a remarkable ability of hESCs to home to clinically relevant regions, and to provide important neuroprotective and restorative functions. This is a remarkable finding that should be translated to clinical trials as soon as possible. Furthermore, PIs propose to engineer and support potentially therapeutic stem cells in various ways, including the use of scaffolds that have already been FDA-approved. One of the proposed methods likely represents a strong early candidate for cell-mediated approaches to neural injury. It also represents a synergy between stem cell biology and tissue engineering which is a unique feature of the proposed CIRM Institute. The other areas are equally compelling and there is every reason to believe that this powerful consolidation of neuroscientists will be responsible for major biomedical and clinical successes in the years to come.

Endocrinology is very strong and many investigators are expanding their research programs with an emphasis on protecting transplanted beta cells from immune responses, and also protecting patients from tumorigenicity of residual undifferentiated cells, an important issue with regard to hESCs. It is believed that success in the proposed studies could lead to pilot studies in humans. The remaining programs are meritorious as well; however, the plans for ophthalmology, while an important area, are developed rather poorly. The technology section is a particular strength of the program members who will seek methods for tracking stem cells in vivo in order to assess the accuracy of targeting after implantation, stem cell viability, fate and function.

FORMAL INSTITUTIONAL COLLABORATIONS: This proposal is a model for formal institutional collaboration between four participating institutions. The strength and value of the collaborative history has been underscored by the award of an NIH Blueprint grant jointly to the four institutions that comprise the proposed program, which is one of only three blueprint grants that were awarded by the NIH. Formal institutional collaborations are described briefly and mirror those of the other sections. 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 specifically will assist in such collaborations is missing. The clinical trials programs will rely on expertise at two local hospitals that have extensive experience in the design and management of trials. These are strong and essential collaborations.

CORE SERVICES: The applicants propose excellent core facilities. One core service will be established in the new CIRM facility—an Advanced Vivarium Services Core which will include various imaging modalities. This core will provide training (coordinating with the Education Core). Other important uses are described in the application and appear appropriate and supportive to the overall mission and goals. Other core services that are available but not in the new facility are appropriate and supportive. These include GMP facilities and technology centers that will be close to the clinical setting.

PLANS FOR GROWTH: Rapid growth of clinical applications is anticipated due to the advanced status of much research, particularly in neurology. Plans for growth in Element Z are outstanding with a commitment to large-scale GMP cell culture facilities for scale up of non-hematopoietic stem cells and a clinically compatible biomaterial production facility. Clinical activities are not expected to take place within the proposed CIRM facility but rather in nearby clinical facilities, where expertise exists in the manipulation of the immune system to accept grafts. They plan to expand their range of pre-clinical and clinical applications through the strategic recruiting of investigators focused on the treatment of various conditions. In addition, it is anticipated that investigators, compliance officers, statisticians and other support staff will be needed for conducting clinical trials. Specific numbers and levels of recruitment are not presented nor do they explain in detail where the new investigators and supporting staff will be housed and to what extent the four participating institutions will contribute. Furthermore, the applicant has not suggested an immediate need for a regulatory core to assist in the design and record keeping required for preclinical activities that will be used to support future IND and Investigational Device Exemption (IDE) applications. In addition, the applicant has not indicated the need for identifying new paradigms for assessing the safety and efficacy of stem cells unique to stem cell based therapeutics.

DISCUSSION: Reviewers emphasized that this represents an extremely well thought-out proposal, commending the targeted research areas, the extensive plans for growth, and the connection to a preclinical model center. Investigators participating in this proposal have experience with relevant preclinical models, as evidenced by publications. Reviewers were concerned that the need for regulatory support was mentioned as a future need, but emphasized that such support needs to be in place long before clinical trials start. A minor concern was raised with regard to the specialization of their clinical collaborators, as they may not be able to support some of the targeted disease areas, but reviewers trusted that this would be properly addressed by the applicants. Overall, the reviewers were very enthusiastic about this application, as the proposed studies break away from dogma and aim for a very sophisticated, cutting-edge level.

Use & Contribution

Score: 93

The proposed CIRM building will be located on a site proximal to all four participating member institutions. It will accommodate 21 PIs and will serve as a true “hub” of the local stem cell community. The building is expected to promote and expand the numerous existing diverse, collaborative and multidisciplinary basic, translational and preclinical research programs. 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. However, it is anticipated that the building and its members will promote the extensive, diverse outreach programs that provide all members of the academic, industrial and lay communities with access to stem cell-related resources and educational opportunities.

Based on the design of the facility and program description, it is clear that this is a well organized, integrated group. The creation of interdisciplinary teams is likely but a detailed plan was not presented. The applicant group has an established track record for moving basic research through the translational pipeline with several examples moving to the clinic, and therefore they will likely be successful. Some reviewers commented that a detailed plan was not presented on how these groups would move Basic and Discovery Research to the Preclinical / Translational stage. Others, though, stated that the three Elements X, Y, and Z are well integrated in the focused areas of interest.

The proposed cores are appropriate and necessary. The open laboratory module design and the cores will enable the integration of multi-disciplinary scientists throughout the facility and will augment the cohesiveness of the group. Conference and meeting facilities will be used for seminars, journal clubs, symposia and other events that are designed to bring interested scientists together and to exchange information and ideas. These facilities will also be equipped with video conferencing capabilities. A committee to oversee facilities operations has been established with equal representation from the four institutions, but it is unclear how policies will be developed or deployed. However, funds have been identified for operations and maintenance.

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