Funding opportunities

Executive Summary The aim of this proposal is to develop human embryonic stem cells (hESCs) for both diagnostic and therapeutic purposes to treat stroke. The applicants hope to develop new drug treatments as well as cell-based therapies using transplanted neurons and glia derived from hESCs. They plan to take two approaches: 1) cell transplant and 2) high throughput screening (HTS) platform as disease model for drug screening. Reviewers concurred that stroke provides a widely studied target for SC medicine, with beneficial effects likely from neuroprotection, reduction of inflammation, trophic factor release in addition to any cell replacement mediated by the differentiated progeny of the transplanted SCs. The field has matured to the point where cell transplantation clinical trials are at an advanced stage of planning and will most likely advance SC medicine to the clinic in the next 5 years. However, reviewers felt that this particular application did a poor job of identifying and addressing the steps required to progress to the clinic. In addition, the planning process lacks details and does not clearly define roles for each team member. For example, the applicant does not discuss the appropriate timing, cell source or delivery method in patients with cerebral ischemia. Reviewers felt that a huge amount of primary basic research needs to be done before cell therapy for cerebral ischemia can be considered sufficiently ready for the clinic, and very little of this is outlined in the proposal. One reviewer felt that this was a very disappointing application in that it contains very little in the way of new and innovative approaches to the pathophysiology and or treatment of cerebral ischemia. With respect to the biomarker/drug discovery approach, reviewers felt the idea of using SC-derived neurons and glia for this purpose was an additional merit of the proposal, was innovative and extremely exciting. However, this aspect was poorly developed in the present application, as were the methodologies to be used for the HTS studies. Furthermore, reviewers felt that it was unlikely that any discoveries using this approach could be in the clinic within 5 years. The principal investigator (PI) is an internationally recognized expert in the field of neural biology with an excellent track record, leadership qualities and translational expertise. S/he has extensive experience in drug development and in initiating and directing clinical trials. The PI has published over 350 peer reviewed papers and has been the recipient of a number of prestigious awards. Moreover, s/he has assembled an impressive team of SC biologists, neurosurgeons, clinical neuroscientists and neurologists that would seem to have the expertise to make a fundamental impact in stroke therapy. This was felt to be the main strength of the application. With respect to planning process, reviewers concurred that it is unclear how the proposed studies will lead to significant advances in the field of stroke therapy. It is also unclear how exactly the partners will interact and what their roles in the project will be. In summary, although potentially exciting, the details of the planning application are very poorly outlined, and the panel did not recommend this application for funding. Reviewer One Comments Concept: This is a proposal to apply SC medicine to stroke using two methodologies: 1) SC-derived neurons and glia for cerebral ischemia, with the aim being drug development and/or biomarker discovery that could be moved into the clinic within 4 years; 2) transplantation of human neural SCs into animal models and then patients with stroke, with or without the co-application of small molecules discovered using a high throughput screening (HTS) facility so as to promote SC differentiation into appropriate neuronal and glial subsets. Plausibility of target Stroke provides a widely studied target for SC medicine, with beneficial effects likely from neuroprotection, reduction of inflammation, trophic factor release in addition to any cell replacement mediated by the differentiated progeny of the transplanted SCs. The field has matured to the point where clinical trials are at an advanced stage of planning. Evidence in support of therapeutic concept Rather little is provided in this application. The concept of transplantation into stroke is well established and so can be taken as read. However, the idea of using SC-derived neurons and glia for biomarker/drug discovery studies is extremely exciting although poorly developed in this application, as are the methodologies to be used for the HTS studies. That said, the facilities already in place at these extremely well funded and cutting edge Institutes makes the likelihood of important discoveries very high. Can it go to clinic in 5 years? SC transplantation in stroke can and will go to the clinic in 5 years. It seems unlikely to me that discoveries in the other areas of this grant will be ready for clinical use within this time-frame. Importance of problem and ability to advance SC medicine to the clinic Stroke is clearly a highly important problem that will, as discussed above, advance SC medicine to the clinic in the next 5 years. A merit of this application is that it thinks beyond this step and asks whether SCs can be used either to develop better diagnostic tools or better therapies that could be used in conjunction with transplantation. These do, I think, represent important and exciting potential applications of SC medicine. Principal Investigator: Track record of Principal Investigator Excellent. Translational expertise of Principal Investigator Excellent. Leadership qualities of Principal Investigator Excellent. How good is the team? The team appears to be very strong, with a good balance of basic, applied and clinical research. Will an award enable the team to prepare a competitive application? The team is certainly appropriate for the proposed area of research, but it is not clear that the application they would prepare would move SC therapy into the clinic in any area other than ‘simple’ SC transplantation in stroke. The innovative and original ideas here will, I think, need significant further work to be ready for clinical use. Reviewer Two Comments Concept: Stroke is the third leading cause of death in the United States. Currently, there are no effective treatments once a stroke has occurred and the damage to the brain is complete. In this proposal the investigators will develop hESCs for both diagnostic and therapeutic (transplantation) purposes to treat stroke. The larger goals are to use hESCs-derived neurons and glia as models for cerebral ischemia. This is necessary since preexisting models have been somewhat incomplete and non-predictive and the investigators hope that adequate in vitro model of human neurons and glia containing the appropriate genes will expedite elucidation of underlying pathological mechanisms, as well as performance of HTS of chemical libraries to identify novel therapeutic drugs and biomarkers for diagnosis. Secondly, investigators ultimately hope to plan a transplantation of functionally-active donor SC-derived neurons and/or glia to treat severe cerebral ischemia. Their proposal contains novel approaches that can be used to generate neurons that are resistant to apoptotic cell death and pre-programmed to become neurons or glia. These cells are ultimately to be transplanted into patients with stroke in FDA-approved clinical trials. In their proposal they have assembled a comprehensive interdisciplinary team comprised of SC biologist, neurologist, and neurosurgeons all with clinic trial experience, regulatory experts, chemists, immunologists and toxicologists. This group will be assembled from academia and biotech community in southern California region as well as other regions of California. Principal Investigator: Excellent Planning Approach: Overall this proposal uses a two prong approach to ultimately utilize human SCs as developing tools (largely in vitro) for drug discovery and modeling disease. This certainly could be an incredibly useful tool for drug discovery, there is no question there are great limitations to in vitro ischemia models for predicting responses in vivo with mature neurons and glia as compared to the very immature neurons present in primary culture paradigms. Most importantly for this proposal, the investigator has put together a very well outlined team of California basic and clinical scientists. The team, as detailed in the proposal, would meet weekly, although details of the disease planning process are not nearly as complete and as well outlined as is needed to evaluate the process. The scientists included in the proposed team are certainly outstanding and could, if directed properly put together such a proposal, however this disease planning grant does lack substantial details of how a coordinated approach would be envisioned and carried out towards the enactment of a disease planning proposal. In summary-potentially exciting— but the details of the planning grant are very poorly outlined. Reviewer Three Comments Concept: This is a poorly written and overly simple proposal. It lacks fundamental experimental design. It is difficult to determine exactly what SC populations the applicants propose to use other than neural SCs derived from human embryonic SCs (hESCs). The statement within the proposal that “the development of new clinical drugs and/or biomarkers gleaned from these studies will be applied in human clinical trials within four years” seems overly enthusiastic and without much experimental support. The applicants provide very little support for the concept of cell transplantation as a therapy for cerebral ischemia as we do not yet know the appropriate timing, cell source or delivery method in patients with cerebral ischemia. There still remains a huge amount of primary basic research that needs to be done before cell therapy for cerebral ischemia can be envisaged; very little of this is outlined in the proposal. Principal Investigator: The P.I. is an internationally recognized expert in the field of neural biology and has extensive experience in drug development and in initiating and directing clinical trials. He has published over 350 peer reviewed papers and has been the recipient of a number of prestigious awards. The P.I. has assembled an impressive team of SC biologists, neurosurgeons, clinical neuroscientists and neurologists that would seem to have the expertise to make a fundamental impact in stroke therapy. Planning Approach: This is a very disappointing application in that it contains very little in the way of new and innovative approaches to the pathophysiology and or treatment of cerebral ischemia. The proposed studies are weak on detail and methodology. It is unclear to this reviewer how the proposed studies will lead to significant advances in the field of stroke therapy. It is also unclear how exactly the partners will interact and what their roles in the project will be.