Autologous Delivery of Pim-1 Enhanced Cardiac Stem Cells: A Novel Clinical Therapy for Cardiac Muscle Regeneration Post MI

Funding Type: 
Disease Team Research I
Grant Number: 
DR1-01480
ICOC Funds Committed: 
$0
Disease Focus: 
Stroke
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
Cell Line Generation: 
Embryonic Stem Cell
Public Abstract: 
There have been consistent advancements in the prevention and treatment of cardiovascular disease. Despite these advancements and partly due to the increasing age of the human population, heart attacks continue to be a human plague currently affecting 5 million people. Heart attack is the most common cause of hospital admission leading to 300,000 deaths each year in the US. The average 5-year survival for these patients is only 50%. The most aggressive treatment for these patients is heart transplantation but this is limited to only 2,000 patients each year because of a serious lack of suitable donors. Therefore, there is an urgent need for new ways to treat patients suffering from heart failure. In the last 10 years, much work has been done on the use of stem cell therapy for organ failure. Recent reports indicate some successes using stem cell therapies to treat heart attack but only limited, short-term benefit has been seen. {REDACTED} has discovered a new type of stem cell therapy for heart attack. This technique uses stem cells taken from the patient’s own heart. The cells, called adult human cardiac progenitor cells (hCPCs), are modified to produce a protein (Pim-1) known to protect the heart and also found to protect hCPCs after they are returned to the patient’s heart. Animal data shows that Pim-1 modified hCPCs are able to generate new heart tissue that persists for at least 6 months and causes major improvements in the heart’s ability to work. In this proposal, the {REDACTED} will partner with {REDACTED} and his colleagues at {REDACTED}, who are recognized experts in tracking fate of stem cells. They will validate survival of Pim-1 modified hCPCS in small and large animal models using state-of-the-art molecular imaging technologies. The third member of the disease team is {REDACTED}. {REDACTED} exists specifically to advance the Pim-1 technology to the point of evaluation by the Food and Drug Administration (FDA) for potential use in human patients. We anticipate that the work conducted in this proposal will result in an application to FDA for the first human clinical trial using the patient’s own hCPCs, modified to produce Pim-1, as a therapy for heart attack and prevention of subsequent heart failure through the generation of new heart muscle. Funding of this proposal will: 1) Develop procedures for Pim-1 modification in hCPCs, 2) Develop quality-assured procedures and perform clinical quality manufacturing of Pim-1 modified hCPCs, 3) Demonstrate safety and efficacy of these modified hCPCs under quality-assured pre-clinical conditions in large animal models, 4) Design the human clinical trial protocol and related documentation that will be proposed to FDA, 5) Compile all documents required for the submission of the Investigational New Drug Application (IND) to FDA, and 6) Submit the IND to FDA by the end of year 4 of this proposal.
Statement of Benefit to California: 
In 2004, the total healthcare cost in the US was 1.9 trillion dollars and cardiovascular disease ranked as the most costly disease category, accounting for 8.3% of these overall costs. Cardiovascular disease and, in particular, myocardial infarction resulting in congestive heart failure, continues to be the number one cause of death in the US, killing some 300,000 Americans each year. Congestive heart failure is also the leading cause of hospital admissions. There are nearly 5 million Americans who are suffering from this illness, with 550,000 new cases reported annually. Despite recent advances in drug therapies for acute myocardial infarction, the average five-year survival for patients suffering this condition remains only at roughly 50% level. While cardiac transplantation is a well-established treatment for end-stage congestive heart failure, this treatment is limited to only 2,000 patients per year due to a severe and chronic shortage of acceptable donor hearts. As the most populous state, California bears the greatest public health impact of myocardial infarction and congestive heart failure as well, a burden that is only getting heavier as the population ages. Thus, there is a clear need for development of novel therapies for these disease conditions, the development of which will benefit California tremendously, from its population to the state’s public health system and its foundation in biomedical research. One such cutting edge treatment uses the Pim-1 modified cardiac progenitor cell (CPC) technology developed by investigators at {REDACTED}, which has already shown significant promise in relevant animal models of ischemic heart disease. In addition to the cost saving benefits that will be realized by the California healthcare system as a result of the development of this technology, there will also be significant economic development benefits realized by the State. Although biotechnology is a robust business sector in California, this sector is currently suffering from the economic downturn as venture funding dries up and jobs are being lost. Funding of this proposal will directly support existing jobs within California’s biotechnology industry at the firms designated for the development work. All the funds specifically targeting scientific procedures will be reinvested in California, fueling economic growth and recovery in addition to furthering a likely revolutionary treatment of heart failure. This funding will also serve to create new jobs at {REDACTED} and other companies associated with the Pim-1 modified hCPC technology. Synergy can result as other cell therapies using related technologies and targeting other disease areas are likely to develop as a consequence of this funding. These funds will also directly support education and jobs at {REDACTED} coping with painful budget reductions resulting in loss of critical talent and research momentum.
Progress Report: 
  • 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.
  • 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.
  • 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.
  • 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.

© 2013 California Institute for Regenerative Medicine