Public Abstract:
The goal is to advance stem cell therapy into the clinic for the treatment of California residents who have suffered an ischemic stroke and who still are disabled with neurological and movement limitations. Using traditional animal-based testing systems, a variety of neural stem cells will be studied and characterized.
The study will compare the effectiveness for stroke treatment of two-types of neural stem cells. One type is obtained from human neural tissue; the other neural stem cells are derived from human embryonic stem cells.
Both cell types will be studied alone and in combination with stem cells obtained from adult bone marrow. Previous human studies indicate that the bone-marrow derived stem cells support the effectiveness of the neural stem cells for stroke treatment.
The study team members are from collaborating institutions. The team includes experts in growing and manufacturing stem cells, translating medical research into bed-side medical treatment, neurologists and neurosurgeons experienced in the treatment of stroke.
The team will study the neural stem cells at the levels of: (a) molecular genetic and protein expression, (b) the interactions of stem cells with each other, (c) the effects of various biological molecules on differentiation of the stem cells, (d) the movement of stem cells after they are administered to a subject, (e) the combination of stem cell types required for optimal therapeutic outcome in stroke.
Further studies involve administering stem cells either non-invasively by intravenous injections, or invasively by temporary placement of a small tube into the brain through which the stem cells will be delivered.
The safety of the stem cells for treatment of strokes will be extensively studied in toxicology and carcinogenicity tests. Once safety has been established, the team will file an application with the US Food and Drug Administration for a license to begin testing the stem cells in California residents who have had strokes and suffer from on-going neurological and movement limitations.
Statement of Benefit to California:
The Planning Group seeks to accelerate the development of a safe and efficacious stem cell therapy for treating those afflicted by stroke. The results of this research initiative will provide significant and measurable benefits to the State of California and its health care system by:
1. Restoring the quality of life to thousands of individuals, their families and caretakers.
2. Reducing the short-term and long-term private and public costs associated with treatment, care and rehabilitation.
3. Serving as a model for collaboration between the private and public sectors
4. Making California a ‘magnet’ for world-renowned researchers and grant money to further regenerative medical research.
According to the California Department of Health Services, stroke is the third leading cause of death in America and the number one cause of adult disability. In 2005, an estimated 9.1% of the population aged 65 or older in California was reported to be affected by stroke. The estimated costs for the treatment and prevention programs in the State are estimated to be in excess of $6.84 billion in both direct and indirect costs. It is estimated that IS accounts for approximately seventy-five percent of the overall costs.
These economic costs do not account for the overall time and emotional burden that families face each and every day when someone within their family has been affected by stroke. As our State’s population ages, and as high blood pressure, hypertension, poor diet, lack of exercise and obesity increase in our general population, so too will the incidence of stroke rise. Therefore, the need to find ways to treat individuals who have already had a first stroke is critical to lessening the economic and social burden on California and its citizens.
An increasing number of pre-clinical and clinical studies, (including those already conducted by team members), provide evidence that stem cell therapy improves functional outcome after ischemic brain damage, even in patients who have experienced stroke several years prior to treatment. The depth and breadth of academic and industry experience and contacts of the Planning Team will accelerate a timely, scientifically-supported clinical pathway to FDA approval.
With the full and active support of the CIRM, this Planning Group believes the State of California and its citizens will benefit in a myriad of ways through the advancement of stem cell therapy for those afflicted by ischemic stroke.
Review Summary:
Executive Summary
The overall goal for this disease team planning award is to advance stem cell (SC) therapy into the clinic by defining a particular cell formulation for the treatment of ischemic stroke. The investigators propose to conduct parallel evaluations of two types of neural stem cells (NSCs) for the treatment of stroke:
1) previously characterized human tissue-derived NSC grown under different conditions and 2) human embryonic stem cell (hESC)-derived NSC. Both cell types would be studied alone and in combination with stem cells derived from adult bone marrow (BM). Adult BM cells appear to play a supportive role to NSCs, both in preclinical models and in stroke patients. The overall team plan will include experts in SC biology, culture manufacturing, translational medicine, regulatory affairs, as well as neurologists and neurosurgeons. Ultimately the team will propose to conduct side-by-side comparisons in preclinical models of embryonic-derived or tissue-derived NSC, alone or in combination with bone marrow derived stem cells, to determine the best cell (or cell combination) for therapeutic application in the treatment of cerebral ischemia.
Stroke represents a reasonable and extensively studied target for stem cell medicine. Besides cell replacement mediated by the differentiated progeny of the transplanted SCs, beneficial effects are likely from neuroprotection, reduction of inflammation, and trophic factor release. The field has matured to the point where clinical trials are at an advanced stage of planning in some centers.
This proposal is designed to advance cell based therapy for the treatment of cerebral ischemia. The Principal Investigator (PI) proposes a disease team to test both brain-derived NSCs and those derived from hESCs, either alone or in combination with bone marrow derived stem cells. The basis for this work comes from stem cell transplantation biology conducted over the last 20 years in outside the US. Although stroke remains a major clinical target for cell based therapies, it is uncertain from this proposal how this work will lead to significant clinical advancement.
Overall this is an expansive proposal to combine and examine two different NSC types in combination with bone marrow derived stem cells. The reviewers felt that the feasibility of combining two different SC types for therapeutic purposes was grandiose. There is a lack of detail concerning the pathway from SC to clinic. The unanimous consensus by the review panel in this particular application was that the concept was not well conceived and implicated naivety about the process of developing new therapies. Moreover, though less relevant, the proposed project appears to be an extension of studies previously performed in outside the US that have not been published in peer-reviewed journals.
The Principal Investigator (PI) is a relatively unknown researcher with little background in the field of SC biology. The assembled team has expertise in the field, but it is very unclear as to how exactly this grouping will function. Two excellent neuroscientists in SC biology are listed but, given that both of them have separately submitted applications, the question as to the commitment they could make to this project needs to be addressed. There was little attention to details about team structure and process.
Based on this outline for such a perceived complicated approach, the review panel is not confident that an award will enable the team to prepare a competitive application that could lead to a clinical trial in the next 5 years.
Reviewer One Comments
Concept:
This proposal is designed to advance cell based therapy for the treatment of cerebral ischemia. The group proposes to test both brain derived fetal neural stem cells and those derived from human embryonic stem cells, either alone or in combination with mesenchymal stem cells.
Principal Investigator:
The principal investigator (PI) is a relatively unknown researcher with little background in the field of stem cell biology. The assembled team has expertise in the field of stem cell biology, but it is very unclear as to how exactly this group will function.
Planning Approach:
The basis for this work comes from stem cell transplantation biology conducted over the last 20 years in Russia. Very little of this work has been translated into English. Although stroke remains a major clinical target for cell based therapies, it is uncertain from this proposal how this work will lead to significant clinical advancement.
Reviewer Two Comments
Concept:
This is an application from a Company to assess three different stem cell lines (human fetal neural stem cells, human ES cell-derived neural stem cells and mesenchymal stem cells) in stroke. The work will be performed in collaboration with a Californian academic institution, using a dedicated GMP facility resourced by the Company.
Plausibility of target
Stroke provides a widely studied target for stem cell 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 stem cells. The field has matured to the point where clinical trials are at an advanced stage of planning (by a different company).
Evidence in support of therapeutic concept
The proposed project appears to be an extension of studies previously performed in Russia that have not, as far as I can see, been published in a peer-reviewed journal. However, the work of many other groups does support the therapeutic concept that underlies this application.
Can it go to clinic in 5 years?
Yes.
Stroke represents an important clinical problem that clearly has the ability to advance stem cell medicine into the clinic, with clinical trials already at an advanced stage of planning in other centers.
Principal Investigator:
Track record of Principal Investigator (PI):
The CV reveals a lack of relevant publications in either stem cell biology or medicine. However, in his/her capacity as Vice President of Stemedica, the PI has clearly addressed the issues surrounding GMP facilities and the need to produce high quality cell products.
Translational expertise of Principal Investigator
See above.
Leadership qualities of Principal Investigator
See above.
Planning Approach:
Merit of planning process proposed; is it well thought out?
There is a lack of detail concerning the pathway from stem cell to clinic, and little or no attention appears to have been paid to issues of patient selection, statistics and other concerns surrounding the clinical trial.
How good is the team?
Excellent Neuroscientists in stem cell biology are listed, (ex Lipton and Snyder) but, given that both of them have separately submitted applications on which they are Principal Investigators, the question as to the commitment they could make to this project needs to be addressed.
Will an award enable the team to prepare a competitive application?
Based on this outline, one could not be confident of that.
Reviewer Three Comments
The concept is a reasonable application of stem cell therapy, but does not seem well-worked out. Overall this is an expansive proposal to combine and examine 2 different neuron stem cell types in combination with mesenchymal cells. Certainly this will require an extensive disease planning team since the likelihood of combining two different stem cell types for therapeutic use is extremely grandiose and highly naive about the process of developing new therapies. To that end the investigator has put a team together that includes Dr. Lipton and E. Snyder who seem to be present in multiple other disease planning grants that seem to overlap between other approaches for using stem cells and stroke as well as number of other neurologists and including Dr. Levy at UCSD and neurosurgeon Dr. Rahul Jandial. The design of this disease planning grant is not well described and a number of members are just listed, there are few details about the sequential approach to planning this grant and team approach to this disease oriented stem cell team other then very crude and superficial outlines of these steps including culturing, compared analysis and data collection. Overall this is a poorly outlined disease planning proposal with little attention to details about a team, timelines, repeated meetings and structure. This lack of attention to details does not provide one with great confidence for a future coordinated plan from such a complicated approach.
