Disease Team Research I
The goal of this project is to produce a stem cell-based therapy for stroke (also known as an ischemic cerebral infarct) that moves into human clinical trials within four years. Stroke is the third leading cause of death in the USA, and a leading cause of disability among adults. Currently, there are no effective treatments once a stroke has occurred (termed completed stroke). In this proposal we aim to develop human stem cells for therapeutic transplantation to treat stroke within the four-year period of the grant. Potential benefits will outweigh risks because only patients with severe strokes that have compromised activities of daily living to an extreme degree will initially be treated. Currently, there are no effective treatments once a stroke has occurred. In this proposal we will develop human stem cells for therapeutic transplantation to treat stroke. Using a novel approach, we will generate stem cells that do not form tumors, but instead only make new nerve cells. We will give drugs to avoid rejection of the transplanted cells. Thus, the treatment should be safe. We will first test the cells in stroke models in rodents (mice) in preparation for a human clinical trial. We will collect a great deal of data on the mice to determine if the stem cells indeed become new nerve to replace the damaged tissue and to assess if the behavior of the mice has improved. We will perform safety and toxicology testing of the cells in two animal species, including mice and a large animal model, as required by the FDA. A comprehensive, interdisciplinary team, comprised of stem cell biologists, neuropathologists, neurobehaviorists, neurologists and neurosurgeons with clinical trial experience, FDA regulatory experts, statisticians, and immunologists has been assembled from academia and the biotech community of different regions of California to fulfill the aims of this proposal. With this Disease Team participating in frequent meetings with the FDA, we intend to file an NID for a stem cell-based therapeutic for stroke within four years time.
Statement of Benefit to California:
Stroke (cerebral ischemia) is the third leading cause of death in California and in all states in the USA, and a leading cause of disability among adults. Currently, there are no effective treatments once a stroke has occurred (termed completed stroke). Hence, many Californians are affected by stroke and because of this can no longer work, socialize with their family or friends, or enjoy life. The profound effect on family members of a stroke victim is also not to be minimized, since they must change their own life in order to care for their loved one who has suffered a stroke. Moreover, even Californians in families who have not suffered from a stroke are affected because they are directly or indirectly paying for the care of stroke victims who end up on welfare. Hence, both the human and economic burden of stroke is tremendous. In this proposal we aim to develop human stem cells for therapeutic transplantation to treat stroke patients within the four-year period of the grant. With such therapy we feel that we can improve the plight of stroke victims. We also believe that an effective, straightforward, and broadly understandable way to describe the benefits of this proposal to the citizens of the State of California is to couch the work in the business concept of “Return on Investment.” The novel therapy for stroke that will be developed as a result of our research program will provide direct benefits to the health of California citizens. In addition, this program and its many complementary programs will generate potentially very large, tangible monetary benefits to the citizens of California. These financial benefits will derive from two sources. The first source will be the sale and licensing of the intellectual property rights that will accrue to the state and its citizens from this research program if financed by CIRM. The second source will be the many different kinds of tax revenues that will be generated from the increased bioscience and biomanufacturing businesses that will be active in California because of the success of this CIRM proposal.
The goal of this project is to produce a stem cell (SC)-based therapy for ischemic stroke that moves into human clinical trials within four years. Stroke (cerebral ischemia) is the third leading cause of death in the USA. Currently, there are no effective treatments once a stroke has occurred. The applicants propose to generate human neuronal stem/progenitor cells (hNPCs) from human embryonic stem cell lines (hESCs) that will carry adenoviral vectors expressing a constitutively active form of a neurogenic transcription factor. The authors hypothesize that this factor will push the cells towards a neuronal progenitor cell fate and concomitantly minimize the risk of teratoma formation. The applicants plan to inject the cells via a stereotactic approach into the affected region after stroke. The plan is to test the scalability of the process under current Good Manufacturing Practices (cGMP). Year 1 outcomes include the generation and characterization of the hESC lines under cGMP conditions, transduction of the hNPCs and finally assessments of neurogenesis in preclinical models of stroke. Year 2 will focus on testing the cGMP facility-produced cells for efficacy and exploring the need for immunosuppression. If no improvement is noted in behavioral outcomes and engraftment, then they will change to work on a mesenchymal stem cell (MSC) based protocol. Year 3 will extend these studies to a second preclinical model under good laboratory practices (GLP). The final year will be dedicated to completing the studies and filing of an investigational new drug application (IND) with the Food and Drug Administration (FDA). Overall, the reviewers agreed that the scientific rationale for the proposal is sound but noted a number of critical weaknesses that led them to doubt its feasibility. Moreover, the alternative approach with MSCs was viewed as a substantial departure from the main proposal and was considered neither compelling nor clinically competitive. In terms of the research design, reviewers were disturbed by inadequacies in the plans for immunosuppression, the suboptimal choices of outcome measures and a perceived deficiency of expertise in the areas of stroke-neurosurgery and transplantation. The combined impact of these concerns led reviewers to conclude that this proposal should not be recommended for funding at this stage. Reviewers generally agreed that the pursuit of neural replacement using neural progenitor cell therapies is a sound rationale. Furthermore, the use of genetic engineering to produce hNPCs that can give rise to apoptosis-resistant neurons was considered novel. In terms of impact, reviewers agreed that a successful cell restorative therapy for stroke would have transformative potential, as there is currently no therapy for the disabling effects derived from the loss of neurological function. Furthermore, the ability to derive improved hNPC lines could have broader implications on the development of therapy for other types of neurological dysfunction. One reviewer found that the most innovative part of the proposal was the use of hESCs as the starting point to derive a stable, transformed neural progenitor cell line that preferentially differentiates into neuronal phenotypes. Other reviewers agreed that this is an attractive proposition, as these cells will have reached their final phenotype and would therefore be much less likely to proliferate and give rise to teratomas. One reviewer, however, questioned the mechanism of action, noting that previous evidence of recovery in animal models of stroke from SC has been mainly attributed to the trophic and neuroprotective effects of the grafted cells rather than their direct incorporation into new tissues. Moreover, this reviewer was concerned about the fact that although the majority of cells will differentiate into neurons, no data was presented describing the types of neurons that they become or the risk that they might present if they migrate away from the site of injury. Still, this reviewer agreed that although neuronal circuitry restoration may not be the principal mechanism of functional recovery, it may still play an important role and serve as a necessary complement to the trophic and neuroprotective effects of cell therapy. The reviewers identified a number of deficiencies in the preliminary data that significantly diminished their enthusiasm and questioned this project’s maturity. While they were encouraged by the strength of the cell biological studies, they were much less enthusiastic about the efficacy data, which was largely limited to fear-shock behavioral outcomes rather than a comprehensive panel of functional measurements. This was thought to be in direct contrast to the recommendations from the STEPS conference and publications that describe the need for a full battery of somatosensory, motor, and memory assays (Stem Cell Therapies as an Emerging Paradigm in Stroke. Stroke 40: 510-515, 2009). Without this critical proof of concept, the reviewers doubted the potential for this effort to advance to an IND application within 4 years. Reviewers found the objectives of the proposal not to be fully achievable. Specifically, they identified flaws in the development of efficacy data, the scalability of the product and some gaps in the translational work. One reviewer found that a relative weakness of this proposal is the reliance on one cell type, which can fail at several critical junctions of the project. Of particular concern is the rate of survival of the cells after transplantation into an adverse ischemic environment. On the other hand, the alternative approach proposed with MSCs was found to be a substantial departure in terms of cell type and purported mechanism of action. Furthermore, the plan with MSCs may no longer represent a novel and innovative Disease Teams application, as that approach is already being tested currently in Phase I clinical trials. In terms of design and feasibility of the research plan, reviewers identified several crucial elements that were missing or insufficiently addressed. First, a number of practical milestones and variables that would be necessary to submit an IND were not considered. For example, for functional analysis of the delivery system, the FDA would expect viability and potency data for the cells using the concentration and flow rates that were proposed. In addition, many details of the GMP manufacturing requirements were inadequately discussed, such as plans for cell banking and for clinical grade production of the virus. The proposed efficacy assays were also considered suboptimal in terms of reflecting the more complex, sensimotor defects that are characteristic of the human condition. The reviewers also desired a more extensive analysis of ultrastructural effects of the proposed therapy in order to more thoroughly assess its mechanism of action. Another major concern shared by the reviewers was the inadequate attention afforded to immunosuppression. One reviewer suggested that if immunosuppression is planned for either MSC or NPC approaches, there should be substantial preclinical work that is not proposed in the application. Further, another reviewer suggested a need for a pre-cell therapy study to determine if there is an infectious morbidity (or therapeutic benefit) associated with the use of immunosuppression alone. This issue will need to be addressed at some level since stroke induces an immunocompromised state, and infections are a major cause of post-stroke morbidity and mortality. One reviewer also found it incumbent upon the team to determine the need and effects of early withdrawal of immunosuppression if severe infections necessitate it. Reviewers indicated that the timelines for the development of clinical grade neurons for transplantation under GMP settings were realistic. There were mixed opinions, however, as to whether those dedicated for preclinical efficacy testing would be feasible, particularly in the case of the larger model. Others felt that the proposed studies would likely need to be lengthened in order to collect longer-term measurements of transplanted cell fate. Reviewers agreed that further consideration should have been given to the potential need for assessing safety and efficacy in a large preclinical model prior to IND filing. Reviewers noted that the PI is extensively published in the field. Moreover, s/he has an international reputation as a leader in the field of molecular mechanisms of neurodegenerative diseases and stroke. The research team has extensive experience in cell biology techniques and the ability to modify and manipulate the allogeneic cell transplants as described. Appropriate effort is allocated to the project, and the team members have a long standing track record of productivity and collaboration with excellent results. Despite this, reviewers found that there was a major gap in the team structure on the clinical-translation side. Specifically, the neurosurgical support team member doesn’t list any interventional trial background, and s/he doesn’t appear to have any special expertise in stroke, or stereotactic interventions. Reviewers acknowledge that there is a collaborator in the team with a wealth of clinical interventional trial experience with stroke; however, this collaborator is not a neuro-interventional radiologist/cerebrovascular interventional neurosurgeon. Another major concern of the team composition is the lack of transplantation experience, and this may become an issue if the patients in the proposed Phase I study require immunosuppression. This is not trivial; especially since nosocomial infections and stroke-induced immunosuppression are major complicating issues that could require the withdrawal of the immunosuppressive drugs prior to or during engraftment. Reviewers found the budget reasonable as outlined, however some reviewers emphasized some vagaries due to the alternative plan with MSCs that would alter the expenditures. The leadership plan was thought to be reasonable. The resources and environment were considered outstanding and the appropriate collaborations with industry for cGMP production appeared to be in place. Overall, while the reviewers agreed that the scientific rationale for the proposal is sound, they noted a number of critical weaknesses that led them to doubt its feasibility. Moreover, the alternative approach with MSCs was viewed as a substantial departure from the main proposal and was considered neither compelling nor clinically competitive. In terms of the research design, reviewers were disturbed by inadequacies in the plans for immunosuppression, the suboptimal choices of outcome measures and an apparent deficiency of expertise in the areas of stroke-neurosurgery and transplantation. The combined impact of these concerns led reviewers to conclude that this proposal should not be recommended for funding at this stage.