Optimizing human embryonic stem cell-derived neural stem/progenitor cells for stroke cell therapy

Funding Type: 
SEED Grant
Grant Number: 
RS1-00434
ICOC Funds Committed: 
$0
Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 
Stroke has the highest annual incidence of any neurological disorder, it affects more people than Alzheimer’s disease, traumatic brain injury, epilepsy and Parkinson’s disease. In the United States, more than 750,000 individuals suffer from stroke every year. There are also approximately 5.4 million stroke survivors and about one-third of them are unable to care for themselves and almost 75% are impaired in some activities of their daily life. The estimated economic burden from stroke exceeds $56.8 billion per year in the United States. Due to the lack of effective therapies, these numbers will increase in the future. A recent study reports that the total cost of stroke from 2005-2050 in the US is projected to top $2 trillion dollars. Currently the only approved stroke treatment is a type of drug called a thrombolytic that breaks up the blood clot that caused the stroke. This drug is only effective within three hours after the clot forms and before severe brain damage can occur. However, if the stroke victim has a pre-existing medical condition, then thrombolytic treatment is too risky because it may cause excessive bleeding. Thus, only 1-4% of stroke patients are eligible and benefit from this treatment. Regenerative medicine is developing as a promising approach to repair diseased or injured brain through stem cell-based therapy. The rationale behind such an approach is to replace lost neural cells and allow or enhance the re-establishment of tissue function. Recent studies have demonstrated that multiple cell types can reverse behavioral deficits in animal models of stroke. However, unlike the human embryonic stem cells (hESCs), these cells are neither suitable for large-scale production nor for the appropriate quality assurance program needed to safely treat a sufficient patient population in multi-center clinical trials. In humans, the safety of the cell transplantation procedure has been demonstrated. The research proposed in this application aims to fill the void in therapeutic options by developing a suitable neural stem/progenitor cell lines (NSPCs) from the hESCs and by establishing parameters to safely transplant these neural cells into patient’s brain to repair tissue damages caused by stroke. This will be achieved by first studying how the hESCs behave in the culture dishes and by isolating the NSPCs from them. We will then make sure that the neurons produced are functional and non tumorigenic. Then, we will test the safety and efficacy of these functional neurons to restore the function of the stroke damaged neural tissue. If successful, the hESCs-derived NSPCs will represent a technically innovative and a viable option for clinical studies.
Statement of Benefit to California: 
Stroke has the highest annual incidence of any neurological disorder, it affects more people than Alzheimer’s disease, traumatic brain injury, epilepsy and Parkinson’s disease. In the United States, more than 750,000 individuals suffer from stroke every year. There are also approximately 5.4 million stroke survivors and about one-third of them are unable to care for themselves and almost 75% are impaired in some activities of their daily life. The estimated economic burden from stroke exceeds $56.8 billion per year in the United States. Due to the lack of effective therapies, these numbers will increase in the future. A recent study reports that the total cost of stroke from 2005-2050 in the US is projected to top $2 trillion dollars. Currently the only approved stroke treatment is a type of drug called a thrombolytic that breaks up the blood clot that caused the stroke. This drug is only effective within three hours after the clot forms and before severe brain damage can occur. However, if the stroke victim has a pre-existing medical condition, then thrombolytic treatment is too risky because it may cause excessive bleeding. Thus, only 1-4% of stroke patients are eligible and benefit from this treatment. Regenerative medicine is developing as a promising approach to repair diseased or injured brain cells through stem cell-based therapy. The rationale is to replace lost brain cells and allow or improve the re-establishment of tissue function. Recent study results in animal models of stroke are encouraging us to move this research forward. In humans, the safety of the concept of cell transplantation has been demonstrated. However, further studies are hampered by the need to find an ideal cell line that is not only safe and improves the patient’s medical condition but one that also can be economically produced in large scale for clinical use. Our research is developing neural cell lines from human embryonic stem cells (hESCs) for their transplantation into a patient’s brain to repair tissue damaged by stroke. If successful, these cells will be valuable as a viable option for clinical studies. Californians who suffer from a stroke and those who care for them would benefit from this therapy that can potentially enhance the patient’s motor function and make them less dependent. This will improve the California health care system and reduce the long-term health care cost burden. In addition, the development of stem cell-based therapies and the intellectual property behind them will benefit California’s economy by creating jobs and treatments that will generate substantial tax revenue.
Progress Report: 
  • A central goal of our CIRM SEED proposal was to use innovative unbiased approaches to discover novel proteins that turn genes on or off in pluripotent stem cells. An understanding of what are these proteins that act as genetic switches and how they function is of significant importance to efforts to use pluripotent stem cells to model disease states in the lab or to provide a source of cells of therapeutic interest for transplantation. We have been successful in our efforts, in that we identified a novel protein that appears to play an unexpected role in the regulation of gene activity in pluripotent stem cells. In addition, we have identified another protein that is critical to maintain the DNA of pluripotent stem cells is a state accessible to other proteins. Our research is therefore providing an integrated picture of what are the genetic switches that turn genes on or off in pluripotent stem cells, what genes do they regulate, and how is their access to DNA regulated. Some of our results have recently been published, while other research is ongoing. In parallel, we have been very successful at transferring expertise to the biotechnology sector in California. In particular, two highly qualified lab members accepted senior scientist positions at top biotechnology firms in California (iPierian and Genentech).
  • A central goal of our CIRM SEED proposal was to use innovative approaches to discover genes that control human embryonic stem cells, with the idea that this knowledge may lead to improved methods for growth and/or differentiation of human pluripotent stem cells in a clinical setting. In the past year we have continued to make significant progress on these efforts. We have found a factor that acts to turn other genes on or off and is active in embryonic stem cells. We have put a considerable amount of effort into optimizing methods to identify exactly what genes this factor controls. Our results show that this factor directly regulates pluripotency-associated genes. This is remarkable, since this factor had not to date been implicated in the regulation of pluripotency. These results put us in a position to characterize the function of this factor in embryonic stem cells in greater detail. In addition, we are applying knowledge gained from our studies to develop methods to enhance the ease with which human pluripotent stem cells are propagated. Human pluripotent stem cells, including embryonic stem cells and induced pluripotent stem cells, are notoriously more difficult to grow than their mouse counterparts, and this has significantly hampered the ability to use existing human pluripotent stem cells to model disease. We have developed conditions that facilitate the propagation of human pluripotent stem cells in a state that resembles mouse ES cells, where they are easier to propagate and grow more rapidly. These findings, while preliminary, suggest that we have the opportunity to explore a transition of human pluripotent stem cells to a state that is easier to culture and manipulate genetically. Thus, the CIRM SEED award has allowed us to discover a novel regulator of pluripotency genes, and to develop conditions that may lead to improved culture and manipulation of human pluripotent stem cells.

© 2013 California Institute for Regenerative Medicine