A stroke kills brain cells by interrupting blood flow. The most common “ischemic stroke” is due to blockage in blood flow from a clot or narrowing in an artery. Brain cells deprived of oxygen can die within minutes. The loss of physical and mental functions after stroke is often permanent and includes loss of movement, or motor, control. Stroke is the number one cause of disability, the second leading cause of dementia, and the third leading cause of death in adults. Lack of movement or motor control leads to job loss and withdrawal from pre-stroke community interactions in most patients and institutionalization in up to one-third of stroke victims. The most effective treatment for stroke, thrombolytics or “clot-busters”, can be administered only within 4.5 hours of the onset of stroke. This narrow time window severely limits the number of stroke victims that may benefit from this treatment. This proposal develops a new therapy for stroke based on embryonic stem cells. Because our (and others’) laboratory research has shown that stem cells can augment the brain’s natural repair processes after stroke, these cells widen the stroke treatment opportunity by targeting the restorative or recovery phase (weeks or months after stroke instead of several hours).
Embryonic stem cells can grow in a culture dish, but have the ability to produce any tissue in the body. We have developed a technique that allows us to restrict the potential of embryonic stem cells to producing cell types that are found in the brain, making them “neural stem cells”. These are more appropriate for treating stroke and may have lower potential for forming tumors. When these neural stem cells are transplanted into the brains of mice or rats one week after a stroke, the animals are able to regain strength in their limbs. Based on these findings, we propose in this grant to further develop these neural stem cells into a clinical development program for stroke in humans at the end of this grant period.
A multidisciplinary team is working rigorously to test the effectiveness of stem cell delivery in several models of stroke, while simultaneously developing processes for the precise manufacture, testing and regulatory approval of a stem cell therapy intended for human use. Each step in this process consists of definite milestones that are being achieved, providing measurable assessment of progress toward therapy development. To accomplish this task, the team consists of stroke physician/scientists, pharmacologists, toxicologists, experts in FDA regulatory approval and key collaborations with a biotechnology manufacturer active in this area. This California-based team has a track record of close interactions and brings prior stroke clinical trial and basic science experience to the proposed translation of a stem cell therapy for stroke.
In the first year of this program, the cells have been translated from an encouraging research level to a product which can be manufactured under conditions suitable for human administration. This has included optimization of the production process, development of reliable tests to confirm cell identity and function, and characterization of the cells utilizing these tests. In animal models in two additional laboratories , improvement in motor function following stroke has been confirmed. The method of administration has also been carefully studied. It has been determined that the cells will be administered around the area of stroke injury rather than directly into the middle of the stroke area. These results encourage the translation of this product from research into clinical trials for the treatment of motor deficit following stroke.
Reporting Period:
Year 2
A stroke kills brain cells by interrupting blood flow. The most common “ischemic stroke” is due to blockage in blood flow from a clot or narrowing in an artery. Brain cells deprived of oxygen can die within minutes. The loss of physical and mental functions after stroke is often permanent and includes loss of movement, or motor, control. Stroke is the number one cause of disability, the second leading cause of dementia, and the third leading cause of death in adults. Lack of movement or motor control leads to job loss and withdrawal from pre-stroke community interactions in most patients and institutionalization in up to one-third of stroke victims. The most effective treatment for stroke, thrombolytics or “clot-busters”, can be administered only within 4.5 hours of the onset of stroke. This narrow time window severely limits the number of stroke victims that may benefit from this treatment. This proposal develops a new therapy for stroke based on embryonic stem cells. Because our (and others’) laboratory research has shown that stem cells can augment the brain’s natural repair processes after stroke, these cells widen the stroke treatment opportunity by targeting the restorative or recovery phase (weeks or months after stroke instead of several hours).
Embryonic stem cells can grow in a culture dish, but have the ability to produce any tissue in the body. We have developed a technique that allows us to restrict the potential of embryonic stem cells to producing cell types that are found in the brain, making them “neural stem cells”. These are more appropriate for treating stroke and may have lower potential for forming tumors. When these neural stem cells are transplanted into the brains of mice or rats one week after a stroke, the animals are able to regain strength in their limbs. Based on these findings, we propose in this grant to further develop these neural stem cells into a clinical development program for stroke in humans at the end
of this grant period.
A multidisciplinary team is working rigorously to test the effectiveness of stem cell delivery in several models of stroke, while simultaneously developing processes for the precise manufacture, testing and regulatory approval of a stem cell therapy intended for human use. Each step in this process consists
of definite milestones that are being achieved, providing measurable assessment of progress toward therapy development. To accomplish this task, the team consists of stroke physician/scientists, pharmacologists, toxicologists, experts in FDA regulatory approval and key collaborations with a biotechnology manufacturer active in this area. This California-based team has a track record of close interactions and brings prior stroke clinical trial and basic science experience to the proposed translation of a stem cell therapy for stroke.
Reporting Period:
Year 3
A stroke kills brain cells by interrupting blood flow. The most common “ischemic stroke” is due to blockage in blood flow from a clot or narrowing in an artery. Brain cells deprived of oxygen can die within minutes. The loss of physical and mental functions after stroke is often permanent and includes loss of movement, or motor control. Stroke is the number one cause of disability, the second leading cause of dementia, and the third leading cause of death in adults. Lack of movement or motor control leads to job loss and withdrawal from pre-stroke community interactions in most patients and institutionalization in up to one-third of stroke victims. The most effective treatment for stroke, thrombolytics or “clot-busters”, can be administered only within 4.5 hours of the onset of stroke. This narrow time window severely limits the number of stroke victims that may benefit from this treatment. This proposal develops a new therapy for stroke based on embryonic stem cells. Because our (and others’) laboratory research has shown that stem cells can augment the brain’s natural repair processes after stroke, these cells widen the stroke treatment opportunity by targeting the restorative or recovery phase (weeks or months after stroke instead of several hours).
Embryonic stem cells can grow in a culture dish, but have the ability to produce any tissue in the body. We have developed a technique that allows us to restrict the potential of embryonic stem cells to producing cell types that are found in the brain, making them “neural stem cells”. These are more appropriate for treating stroke and may have lower potential for forming tumors. When these neural stem cells are transplanted into the brains of mice or rats one week after a stroke, the animals are able to regain strength in their limbs. Based on these findings this grant is supporting conduct of IND-enabling work to initiate a clinical development program for stroke in humans by the end of this grant period.
A multidisciplinary team is working rigorously to test the effectiveness of stem cell delivery in several models of stroke, while enabling precise manufacture, testing and regulatory clearance of a first in human clinical trial. Defined milestones are being achieved, providing measurable assessment of progress toward therapy development. Definitive manufacturing and pharmacology studies are underway and regulatory filings are in progress. The team consists of stroke physician/scientists, pharmacologists, toxicologists, experts in FDA regulatory and key collaborations with a biotechnology manufacturer active in this area. This California-based team has a track record of close interactions and brings prior stroke clinical trial and basic science experience to the proposed translation of a stem cell therapy for stroke.
Reporting Period:
Year 4
A stroke kills brain cells by interrupting blood flow. The most common 'ischemic stroke' is due to blockage in blood flow from a clot or narrowing in an artery. Brain cells deprived of oxygen can die within minutes. The loss of physical and mental functions after stroke is often permanent and includes loss of movement, or motor, control. Stroke is the number one cause of disability, the second leading cause of dementia, and the third leading cause of death in adults. Lack of movement or motor control leads to job loss and withdrawal from pre-stroke community interactions in most patients and institutionalization in up to one-third of stroke victims. The most effective treatment for stroke, thrombolytics or 'clot-busters', can be administered only within 4.5 hours of the onset of stroke. This narrow time window severely limits the number of stroke victims that may benefit from this treatment. This proposal develops a new therapy for stroke based on embryonic stem cells. Because our (and others') laboratory research has shown that stem cells can augment the brain's natural repair processes after stroke, these cells widen the stroke treatment opportunity by targeting the restorative or recovery phase (weeks or months after stroke instead of several hours).
Embryonic stem cells can grow in a culture dish, but have the ability to produce any tissue in the body. We have developed a technique that allows us to restrict the potential of embryonic stem cells to producing cell types that are found in the brain, making them 'neural stem cells'. These are more appropriate for treating stroke and may have lower potential for forming tumors. When these neural stem cells are transplanted into the brains of mice or rats one week after a stroke, the animals are able to regain strength in their limbs. Based on these findings this grant is supporting conduct of IND-enabling work to initiate a clinical development program for stroke in humans by the end of this grant period.
A multidisciplinary team is working to test the effectiveness of stem cell delivery in several models of stroke, while enabling precise manufacture, testing and regulatory clearance of a first in human clinical trial. Defined milestones are being achieved, providing measurable assessment of progress toward therapy development. Definitive manufacturing and pharmacology studies are underway and regulatory filings are in progress. The team consists of stroke physicians/scientists, pharmacologists, toxicologists, experts in FDA regulatory and key collaborations with a biotechnology manufacturer active in this area. This California-based team has a track record of close interactions and brings prior stroke clinical trial and basic science experience to the proposed translation of a stem cell therapy for stroke.
Reporting Period:
Year 5 (NCE)
PUBLIC SUMMARY OF SCIENTIFIC PROGRESS
A stroke kills brain cells by interrupting blood flow. The most common “ischemic stroke” is due to blockage in blood flow from a clot or narrowing in an artery. Brain cells deprived of oxygen can die
within minutes. The loss of physical and mental functions after stroke is often permanent and includes loss of movement, or motor, control. Stroke is the number one cause of disability, the second leading
cause of dementia, and the third leading cause of death in adults. Lack of movement or motor control leads to job loss and withdrawal from pre-stroke community interactions in most patients and
institutionalization in up to one-third of stroke victims. The most effective treatment for stroke, thrombolytics or “clot-busters”, can be administered only within 4.5 hours of the onset of stroke. This
narrow time window severely limits the number of stroke victims that may benefit from this treatment. This proposal develops a new therapy for stroke based on embryonic stem cells. Because
our (and others’) laboratory research has shown that stem cells can augment the brain’s natural repair processes after stroke, these cells widen the stroke treatment opportunity by targeting the
restorative or recovery phase (weeks or months after stroke instead of several hours).
Embryonic stem cells can grow in a culture dish, but have the ability to produce any tissue in the body. We have developed a technique that allows us to restrict the potential of embryonic stem cells
to producing cell types that are found in the brain, making them “neural stem cells”. These are more appropriate for treating stroke and may have lower potential for forming tumors. When these neural stem cells are transplanted into the brains of mice or rats one week after a stroke, the animals are able to regain strength in their limbs. Based on these findings this grant is supporting conduct of IND-enabling work to initiate a clinical development program for stroke in humans by the end of this grant period.
A multidisciplinary team is working to test the effectiveness of stem cell delivery in several models of stroke, while enabling precise manufacture, testing and regulatory clearance of a first in human clinical trial. Defined milestones are being achieved, providing measurable assessment of progress toward therapy development. Definitive manufacturing and pharmacology studies are underway and regulatory filings are in progress. The team consists of stroke physician/scientists, pharmacologists, toxicologists, experts in FDA regulatory and key collaborations with a biotechnology manufacturer active in this area. This California-based team has a track record of close interactions and brings prior stroke clinical trial and basic science experience to the proposed translation of a stem cell therapy for stroke.
Grant Application Details
Application Title:
Embryonic-Derived Neural Stem Cells for Treatment of Motor Sequelae following Sub-cortical Stroke
Public Abstract:
A stroke kills brain cells by interrupting blood flow. The most common “ischemic stroke” is due to blockage in blood flow from a clot or narrowing in an artery. Brain cells deprived of oxygen can die within minutes. The loss of physical and mental functions after stroke is often permanent and includes loss of movement, or motor, control. Stroke is the number one cause of disability, the second leading cause of dementia, and the third leading cause of death in adults. Lack of movement or motor control leads to job loss and withdrawal from pre-stroke community interactions in most patients and institutionalization in up to one-third of stroke victims. The most effective treatment for stroke, thrombolytics or “clot-busters”, can be administered only within 4.5 hours of the onset of stroke. This narrow time window severely limits the number of stroke victims that may benefit from this treatment. This proposal develops a new therapy for stroke based on embryonic stem cells. Because our (and others’) laboratory research has shown that stem cells can augment the brain’s natural repair processes after stroke, these cells widen the stroke treatment opportunity by targeting the restorative or recovery phase (weeks or months after stroke instead of several hours).
Embryonic stem cells can grow in a culture dish, but have the ability to produce any tissue in the body. We have developed a technique that allows us to restrict the potential of embryonic stem cells to producing cell types that are found in the brain, making them “neural stem cells”. These are more appropriate for treating stroke and may have lower potential for forming tumors. When these neural stem cells are transplanted into the brains of mice or rats one week after a stroke, the animals are able to regain strength in their limbs. Based on these findings, we propose in this grant to further develop these neural stem cells into a clinical development program for stroke in humans at the end of this grant period.
This proposal develops a multidisciplinary team that will rigorously test the effectiveness of stem cell delivery in several models of stroke, while simultaneously developing processes for the precise manufacture, testing and regulatory approval of a stem cell therapy intended for human use. Each step in this process consists of definite milestones that must be achieved, and provides measurable assessment of progress toward therapy development. To accomplish this task, the team consists of stroke physician/scientists, pharmacologists, toxicologists, experts in FDA regulatory approval and key collaborations with biotechnology firms active in this area. This California-based team has a track record of close interactions and brings prior stroke clinical trial and basic science experience to the proposed translation of a stem cell therapy for stroke.
Statement of Benefit to California:
The State of California has made a historic investment in harnessing the potential of stem cells for regenerative therapy. While initially focused on developing new stem cell technologies, CIRM has recognized that translational progress from laboratory to clinic must also be fostered, for this is ultimately how Californians will benefit from their investment. Our focus on developing a neuro-restorative therapy for treatment of motor sequelae following sub-cortical stroke contains several benefits to California. The foremost benefit will be the development of a novel form of therapy for a major medical burden: The estimated economic burden for stroke exceeds $56.8 billion per year in the US, with 55% of this amount supporting chronic care of stroke survivors (1). While the stroke incidence markedly increases in the next half-century, death rates from stroke have declined. These statistics translate into an expected large increase in disabled stroke survivors (1) that will have a significant impact on many aspects of life for the average Californian. Stroke is the third greatest cause of death, and a leading cause of disability, among Californians. Compared to the nation, California has slightly above average rates for stroke (2). Treatments that improve repair and recovery in stroke will reduce this clinical burden.
The team that has been recruited for this grant is made of uniquely qualified members, some of whom were involved in the development, manufacturing and regulatory aspects of the first clinical trial for safety of neural stem cells for stroke. Thus not only is the proposed work addressing a need that affects most Californians, it will result in the ability to initiate clinical studies of stem cells for stroke recovery from a consortium of academic and biotechnology groups in California.
1. Carmichael, ST. (2008) Themes and strategies for studying the biology of stroke recovery in the poststroke epoch. Stroke 39(4):1380-8.
2. Reynen DJ, Kamigaki AS, Pheatt N, Chaput LA. The Burden of Cardiovascular Disease in California: A Report of the California Heart Disease and Stroke Prevention Program. Sacramento, CA: California Department of Public Health, 2007.
