Neurological Disorders

Coding Dimension ID: 
303
Coding Dimension path name: 
Neurological Disorders

Using human embryonic stem cells to treat radiation-induced stem cell loss: Benefits vs cancer risk

Funding Type: 
SEED Grant
Grant Number: 
RS1-00413
ICOC Funds Committed: 
$625 617
Disease Focus: 
Cancer
Neurological Disorders
Skeletal Muscle
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 
A variety of stem cells exist in humans throughout life and maintain their ability to divide and change into multiple cell types. Different types of adult derived stem cells occur throughout the body, and reside within specific tissues that serve as a reserve pool of cells that can replenish other cells lost due to aging, disease, trauma, chemotherapy or exposure to ionizing radiation. When conditions occur that lead to the depletion of these adult derived stem cells the recovery of normal tissue is impaired and a variety of complications result. For example, we have demonstrated that when neural stem cells are depleted after whole brain irradiation a subsequent deficit in cognition occurs, and that when muscle stem cells are depleted after leg irradiation an accelerated loss of muscle mass occurs. While an increase in stem cell numbers after depletion has been shown to lead to some functional recovery in the irradiated tissue, such recovery is usually very prolonged and generally suboptimal.Ionizing radiation is a physical agent that is effective at reducing the number of adult stem cells in nearly all tissues. Normally people are not exposed to doses of radiation that are cause for concern, however, many people are subjected to significant radiation exposures during the course of clinical radiotherapy. While radiotherapy is a front line treatment for many types of cancer, there are often unavoidable side effects associated with the irradiation of normal tissue that can be linked to the depletion of critical stem cell pools. In addition, many of these side effects pose particular threats to pediatric patients undergoing radiotherapy, since children contain more stem cells and suffer higher absolute losses of these cells after irradiation.Based on the foregoing, we will explore the potential utility and risks associated with using human embryonic stem cells (hESC) in the treatment of certain adverse effects associated with radiation-induced stem cell depletion. Our experiments will directly address whether hESCs can be used to replenish specific populations of stem cells in the brain and muscle depleted after irradiation in efforts to prevent subsequent declines in cognition and muscle mass respectively. In addition to using hESC to hasten the functional recovery of tissue after irradiation, we will also test whether implantation of such unique cells holds unforeseen risks for the development of cancer. Evidence suggests that certain types of stem cells may be prone to cancer, and since little is known regarding this issue with respect to hESC, we feel this critical issue must be addressed. Thus, we will investigate whether hESC implanted into animals develop into tumors over time. The studies proposed here comprise a first step in determining how useful hESCs will be in the treatment of humans exposed to ionizing radiation, as well as many other diseases where adult stem cell depletion might be a concern.
Statement of Benefit to California: 
Radiotherapy is a front line treatment used in California for many types of cancer, including brain, breast, prostate, bone and other cancer types presenting surgical complications. Treatment of these cancers through the use of radiation is however, often associated with side effects caused by the depletion of critical stem cell pools contained within non-cancerous normal tissue. While radiotherapy is clearly beneficial overall, many of these side effects have no viable treatment options. If we can demonstrate that human embryonic stem cells (hESC) hold promise as a safe therapeutic agent for the treatment of radiation-induced stem cell depletion, then cancer patients may have a new treatment for countering many of the debilitating side effects associated with radiotherapy. Once developed this new technology could position California to attract cancer patients throughout the United States, and the state would clearly benefit from the increased economic activity associated with a rise in patient numbers.
Progress Report: 
  • We have undertaken an extensive series of studies to delineate the radiation response of human embryonic stem cells (hESCs) and human neural stem cells (hNSCs) both in vitro and in vivo. These studies are important because radiotherapy is a frontline treatment for primary and secondary (metastatic) brain tumors. While radiotherapy is quite beneficial, it is limited by the tolerance of normal tissue to radiation injury. At clinically relevant exposures, patients often develop variable degrees of cognitive dysfunction that manifest as impaired learning and memory, and that have pronounced adverse effects on quality of life. Thus, our studies have been designed to address this serious complication of cranial irradiation.
  • We have now found that transplanted human embryonic stem cells (hESCs) can rescue radiation-induced cognitive impairment in athymic rats, providing the first evidence that such cells can ameliorate radiation-induced normal-tissue damage in the brain. Four months following head-only irradiation and hESC transplantation, the stem cells were found to have migrated toward specific regions of the brain known to support the development of new brain cells throughout life. Cells migrating toward these specialized neural regions were also found to develop into new brain cells. Cognitive analyses of these animals revealed that the rats who had received stem cells performed better in a standard test of brain function which measures the rats’ reactions to novelty. The data suggests that transplanted hESCs can rescue radiation-induced deficits in learning and memory. Additional work is underway to determine whether the rats’ improved cognitive function was due to the functional integration of transplanted stem cells or whether these cells supported and helped repair the rats’ existing brain cells.
  • The application of stem cell therapies to reduce radiation-induced normal tissue damage is still in its infancy. Our finding that transplanted hESCs can rescue radiation-induced cognitive impairment is significant in this regard, and provides evidence that similar types of approaches hold promise for ameliorating normal-tissue damage throughout other target tissues after irradiation.
  • A comprehensive series of studies was undertaken to determine if/how stem cell transplantation could ameliorate the adverse effects of cranial irradiation, both at the cellular and cognitive levels. These studies are important since radiotherapy to the head remains the only tenable option for the control of primary and metastatic brain tumors. Unfortunately, a devastating side-effect of this treatment involves cognitive decline in ~50% of those patients surviving ≥ 18 months. Pediatric patients treated for brain tumors can lose up to 3 IQ points per year, making the use of irradiation particularly problematic for this patient class. Thus, the purpose of these studies was to determine whether cranial transplantation of stem cells could afford some relief from the cognitive declines typical in patients afflicted with brain tumors, and subjected to cranial radiotherapy. Human embryonic (hESCs) and neural (hNSCs) stem cells were implanted into the brain of rats following head only irradiation. At 1 and 4 months later, rats were tested for cognitive performance using a series of specialized tests designed to determine the extent of radiation injury and the extent that transplanted cells ameliorated any radiation-induced cognitive deficits. These cognitive tasks take advantage of the innate tendency of rats to explore novelty. Successful performance of this task has been shown to rely on intact spatial memory function, a brain function known to be adversely impacted by irradiation. Our data shows that irradiation elicits significant deficits in learning and spatial task recognition 1 and 4-months following irradiation. We have now demonstrated conclusively, and for the first time, that irradiated animals receiving targeted transplantation of hESCs or hNSCs 2-days after, show significant recovery of these radiation induced cognitive decrements. In sum, our data shows the capability of 2 stem cell types (hESC and hNSC) to improve radiation-induced cognitive dysfunction at 1 and 4 months post-grafting, and demonstrates that stem cell based therapies can be used to effectively to reduce a serious complication of cranial irradiation.

Human Embryonic Stem Cells and Remyelination in a Viral Model of Demyelination

Funding Type: 
SEED Grant
Grant Number: 
RS1-00409
ICOC Funds Committed: 
$425 594
Disease Focus: 
Multiple Sclerosis
Neurological Disorders
Immune Disease
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 
Multiple sclerosis (MS) is the most common neurologic disease affecting young adults under the age of 40 with the majority of MS patients diagnosed in the second or third decade of life. MS is characterized by the gradual loss of the myelin sheath that surrounds and insulates axons that allow for the conduction of nerve impulses – a process known as demyelination. For unknown reasons, the ability to remyelinate axons is impaired in MS patients making recovery of motor skills difficult. Therefore, developing novel and effective approaches to remyelinate axons in MS patients would dramatically improve the quality of life of many MS patients. The experiments described in this research proposal utilize a well-accepted model of MS to further characterize the potential clinical applicability of human embryonic stem cells (hESCs) to remyelinate axons. Such knowledge is crucial in order to increase our understanding of stem cells with regards to treatment of numerous human diseases including MS.
Statement of Benefit to California: 
California is the most populated state in the USA. As such, the costs of medical care for the treatment of patients with chronic diseases such as multiple sclerosis (MS) represents a significant and growing problem. MS is the most common neurologic disease affecting young adults under the age of 40 with the majority of MS patients diagnosed in the second or third decade of life. Given the population of California, there are many MS patients living in the state and the numbers will undoubtedly grow. It is unusual for MS patients to die from the disease and many will live normal life spans but will develop an increasing array of medical problems stemming from the progression of neurologic damage associated with MS. MS is characterized by the gradual loss of the myelin sheath that surrounds and insulates axons that allow for the conduction of nerve impulses – a process known as demyelination. For unknown reasons, the ability to remyelinate axons is impaired in MS patients making recovery of motor skills difficult. Therefore, developing novel and effective approaches to remyelinate axons in MS patients would dramatically alleviate some of the burden placed on the medical community by improving the quality of life of many MS patients. The experiments described in this research proposal utilize a well-accepted model of MS to further characterize the potential clinical applicability of human embryonic stem cells (hESCs) to remyelinate axons. Such knowledge is crucial in order to increase our understanding of stem cells with regards to treatment of human diseases with the ultimate goal of limiting patient suffering and reducing medical costs.
Progress Report: 
  • Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that results in demyelination and axonal loss, culminating in extensive disability through defects in neurologic function. The demyelination that defines MS pathology is progressive over time; however, studies indicate that myelin repair can occur during the course of disease in patients with MS and in animal models designed to mimic the immunopathogenesis of MS. While it is generally thought that endogenous oligodendrocyte precursor cells (OPCs) are largely responsible for spontaneous remyelination, it is unclear why these cells are only able to transiently induce myelin repair in the presence of ongoing disease. Along these lines, two therapies for demyelinating diseases look promising; implanting OPCs into sites of neuroinflammation that are directly capable of inducing remyelination of the damaged axons and/or modifying the local environment to stimulate and support remyelination by endogenous OPCs. Indeed, we have shown that human embryonic stem cell (hESC)-derived oligodendrocytes surgically implanted into the spinal cords of mice with virally induced demyelination promoted focal remyelination and axonal sparing. We are currently investigating how the implanted OPCs positionally migrate to areas of on-going demyelination and the role these cells play in repairing the damaged CNS. The purpose of this research is to identify the underlying mechanism(s) responsible for hESC-induced remyelination.
  • Oligodendrocyte progenitor cells (OPCs) are important in mediating remyelination in response to demyelinating lesions. As such, OPCs represent an attractive cell population for use in cell replacement therapies to promote remyelination for treatment of human demyelinating diseases. High-purity OPCs have been generated from hESC and have been shown to initiate remyelination associated with improved motor skills in animal models of demyelination. We have previously determined that engraftment of hESC-derived OPCs into mice with established demyelination does not significantly improve clinical recovery nor reduce the severity of demyelination. Importantly, remyelination is limited following OPC transplantation. These findings highlight that the microenvironment is critical with regards to the remyelination potential of engrafted cells. In addition, we have determined that human OPCs are capable of migrating in response to proinflammatory molecules often associated with human neuroinflammatory diseases such as multiple sclerosis. This is an important observation in that it will likely be necessary for engrafted OPCs to be able to positionally navigate within tissue in order to move from the site of surgical transplantation to areas of damage to initiate repair and tissue remodeling. Finally, we have also made a novel discovery of a unique signaling pathway that protects OPCs from damage/death in response to treatment with proinflammatory cytokines. We believe this is an important and translationally relevant observation as OPCs are critical in contributing to remyelination and remyelination failure is an important clinical feature for many human demyelinating diseases inclusing spinal cord injury and MS. We have identified a putative protective ligand/receptor interaction affords protection from cytokine-induced apoptosis. These findings may reveal novel avenues for therapeutic intervention to prevent damage/death of OPCs and enhance remyelination.

The Immunological Niche: Effect of immunosuppressant drugs on stem cell proliferation, gene expression, and differentiation in a model of spinal cord injury.

Funding Type: 
SEED Grant
Grant Number: 
RS1-00377
ICOC Funds Committed: 
$619 223
Disease Focus: 
Spinal Cord Injury
Neurological Disorders
Stem Cell Use: 
Adult Stem Cell
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 
Our understanding of the effect of immunosuppressive agents on stem cell proliferation and differentiation in the central nervous system is limited. Indeed, even the necessity for long-term immunosuppression to promote the survival of stem cells grafted into the “immunoprivileged” central nervous system (CNS) is unknown. Grafting multipotent stem cells into the injured CNS often results in a failure of the cells to survive. If the cells survive, often they differentiate into astrocytes, a cell-type not considered beneficial. We recently grafted human stem cells (hCNS-SC) into spinal injured mice and observed behavioral improvements coupled with differentiation of these human cells into neurons and oligodendrocytes. We also observed mouse-human synapse formation and remyelination. The mice we used lacked a functional immune system, enabling us to grafting human cells into the mice without the use of immunosuppressants. When these same cells were grafted into spinal injured rats with a normal immune system, we had to immunosuppress the animals. Exposure of these human stem cells to immunosuppressive drugs resulted poor cell survival. The cells that did survive predominantly differentiated into astrocytes. Did the immunosuppressive drugs we used alter the ability of the human stem cells to differentiate into useful cells? All cell-based therapeutic approaches are dependent upon either immunosuppression in an otherwise normal animal or testing for proof of principal in an immunodeficient animal model. This has quite significant implications for animal experiments or human trials, where continuous immunosuppression is required to obtain successful graft survival. No one knows if there are direct effects of immunosuppressant drugs on neural stem cells. Stem cells may also respond differently to immunosuppression depending on their “ontogenetic” age (embryonic vs. fetal vs. adult). There is a common perception that “young” ES cells will have greater potential than “older” stem cells. Stem cells isolated at different ontogenetic stages might respond differently to immunosuppression. We predict that the immunosuppressive drugs will exert direct effects on stem cell proliferation, gene expression, and fate determination, both in cell culture and when grafted into animals with spinal cord injury. We will also test if “ontogenetic” age alters the responsiveness of stem cells.
Statement of Benefit to California: 
The California Institute for Regenerative Medicine (CIRM) recognizes that the field of stem cell biology is in its infancy. CIRM has requested a broad range of research to fill in key gaps in our understanding of basic stem cell biology and the possible use of these cells as therapeutics. Grants are to be judged on impact (extent the proposed research addresses an important problem; significantly moves the field forward scientifically; moves the research closer to therapy; and changes the thinking or experimental practice in the field), quality (is proposed research planned carefully to give a meaningful result; are possible difficulties are acknowledge; does the timetable allows for achieving significant research) and innovation (to what extent the research approach is original, breaks new ground, and brings novel ideas to bear on an important problem). We believe that the projects proposed here target several of the areas CIRM cites as beneficial to the State of California. This proposal addresses the critical area of immunosuppression and stem cell survival in animal transplantation models. Future therapies using human stem cells will have to surmount the possible rejection by the host of cells derived from another source. If traditional immunosuppressive drugs are to be used, we will need to understand whether these drugs have a direct effect on stem cell proliferation and fate determination (or differentiation). Furthermore, these projects will allow for a direct comparison of stem cells from different ontogenetic stages and the ability to improve functional outcome after spinal cord injury. Thus we may gain insight into whether embryonic derived stem cells are more useful than adult derived stem cells as a therapeutic tool.
Progress Report: 
  • We have shown that fetal human central nervous system derived stem cells (HuCNS-SC) transplanted into a mouse model of spinal cord injury (SCI) improve behavioral recovery. Transplanted human cells differentiated into myelinating oligodendrocytes and synapse forming neurons. These data suggest that efficacy is dependent upon successful cell engraftment and appropriate cell fate. The strain of mice (NOD-scid mice) are immunodeficient, which allows transplanted human cell populations to engraft and promote behavioral recovery in the absence of confounds due to a rejection response and allows us to avoid using immunosuppressant drugs. Clinically, however, it is clear that transplantation of therapeutic human cell populations will require administration of immunosuppressants (IS) such as CsA, FK506, or Rapamycin. These immunosuppressants work by altering signaling pathways which are also present within stem cells. Hence, in addition to promoting engraftment, IS have the potential to affect stem cell proliferation and/or differentiation. In Aim 1A, we tested this hypothesis in a cell culture model and found that HuCNS-SC fate and proliferation were altered by exposure to different IS. CsA and FK506 decreased the number of astrocytes in culture compared to control conditions, while Rapamyin increased the number of astrocytes. All three IS increased the number of ß-tubulin III positive neuron-like cells.
  • In Aim 1B, we tested whether cells of the inflammatory system (neutrophils and macrophages) could also directly influence stem cell proliferation and fate. To test this possibility, we exposed either fetal or embryonic neural stem cells to cell culture media from co-cultures of neutrophils or macrophages. We found that neutrophil-mediated release of inflammatory proteins promotes astrocyte differentiation of fetal derived neural stem cells but not embryonic derived neural stem cells. One way inflammatory cells might be working is via oxidative stress (e.g. hydrogen peroxide). Interestingly, excess hydrogen peroxide promoted more extensive cell death of embryonic derived versus fetal fetal derived neural stem cells, suggesting an intrinsic difference in the vulnerably of these two cell populations to oxidative stress. Conditioned media from neutrophils was found to reduce proliferation in fetal neural stem cells but not embryonic derived neural stem cells. In addition, we found neutrophil conditioned media promotes human fetal NSC astrocytic fate and migration towards sites of injury epicenter in an animal model of spinal cord injury; followup cell culture experiments enabled us to determine that neutrophil synthesized complement proteins were having a direct effect on stem cell fate and migration, resulting in a patent filing. These data demonstrate that fetal NSCs and ES-NSCs are very different by nature and nurture.
  • In Aim 2, we evaluated the hypothesis that IS could alter stem cell proliferation and/or fate in vivo, independent of rejection from the recipient’s immune system. HuCNS-SC were transplanted into NOD-scid mice, which have no immune system and hence cannot mount an immune response to the foreign cells. These animals received different immunosuppressants (CsA, FK506, Rapamycin, or vehicle) daily after transplantation until sacrifice 13 weeks later to determine if the total number of surviving human cells, or the end cell fate of the transplanted cells would be altered due to exposure to IS drugs compared to the vehicle control group. Behavioral recovery was assessed via open-field walking assessment, horizontal ladder beam testing, and video based “CatWalk” gait analysis. IS administration did not affect behavioral recovery by any of these measures compared to HuCNS-SC transplanted animals that received vehicle as an IS. Spinal cords were dissected, sectioned, and immunostained using human-specific markers in conjunction with cell lineage/fate and proliferation markers. Cell engraftment, proliferation, and fate were quantified using unbiased methods. The average number of engrafted human cells in uninjured animals was 319,700 vs 214,900 in vehicle treated injured controls. Human cell engraftment in any IS group was not significantly different than vehicle injured controls. Interestingly, 67% of human cells differentiated into Olig2+ oligodendrocyte-like cells in the uninjured controls, while 45% were Olig2 positive in vehicle treated injured controls. IS treatment did not alter Olig2 cell numbers in injured animals. 9% of human cells differentiated into GFAP positive astrocyte-like cells in the uninjured controls, compared with 9% in vehicle treated injured controls. IS treatment did not alter GFAP cell numbers in injured animals. Quantification of proliferation and other lineage markers is ongoing. The important finding thus far is that when administered to whole animals with a human stem cell transplant, a range of immunosuppressant drugs does not appear to significantly alter stem cell fate.

Genetic manipulation of human embryonic stem cells and its application in studying CNS development and repair

Funding Type: 
SEED Grant
Grant Number: 
RS1-00333
ICOC Funds Committed: 
$642 361
Disease Focus: 
Amyotrophic Lateral Sclerosis
Neurological Disorders
Spinal Cord Injury
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 
The advent of human embryonic stem cells (hESCs) has offered enormous potential for regenerative medicine and for basic understanding of human biology. On the one hand, hESCs can be turned into many different cell types in culture dish, and specific cell types derived from hESCs offer an almost infinite source for cellular replacement therapies. This is the primary reason for which hESCs have received much attention from the general public. On the other hand, scientists can study the properties of hESCs and their derivatives, and determine the effect of genes and molecules on such properties either in culture dish or with transplantation studies in live animals. This second aspect of hESC research would not only significantly enhance our understanding of the function of human genes, but will greatly augment our ability to apply hESCs in transplantation therapies and regenerative medicine. To attain the full potential of hESCs, genetic manipulation of hESCs is essential. In this proposal, we will establish the methods to genetically manipulate an increasingly used, non-federally approved hESC line, the HUES-9, and assess the feasibility to use genetically modified HUES-9 cells in cell transplantation studies to assess the integration of hESCs into the mouse central nervous system. We propose to achieve both homologous recombination (i.e. gene targeting) and transgene expression (with bacterial artificial chromosome), which have complementary utilities in assaying gene function in addition to the opportunity to label hESCs or their derivatives with fluorescent markers. Specifically, with genetic engineering of hESCs we will be able to 1) label hESCs and specific cell types derived from hESCs so that they can be readily followed in culture dish and in animals that have received cellular transplants; 2) disturb an endogenous gene or add more copies of a gene so that the effect of a gene of interest can be assessed (for this purpose, a gene involved in the development of a major motor tract, the corticospinal tract, will be studied). We will then transplant genetically engineered hESCs and their derivatives into the embryonic and adult mouse CNS to assess how well these cells integrate into the mouse CNS, and whether such transplanted animals can serve as valid models to study the effect of genes on hESC function in live animals. In transplantation studies involving adult mouse recipients, injured mouse CNS will be used in addition to intact CNS in order to evaluate the potential of hESCs to integrate into injured CNS, which has direct implications on the therapeutic potential of these cells. In summary, our proposal will establish the methods and tools to genetically manipulate HUES-9 cells, explore a paradigm to study human genes and cells in a context of neural development and cellular therapies, and will pave the way for future studies of genes and pathways in basic biology and regenerative medicine with hESCs.
Statement of Benefit to California: 
The disability, loss of earning power, and loss of personal freedom associated with spinal cord injury is devastating for the injured individual, and creates a financial burden of an estimated $400,000,000 annually for the state of California. Research is the only solution as currently there are no cures for spinal cord injury. My lab studies the underlying mechanisms for axon regeneration failure after spinal cord injury using mouse genetics and animal models of spinal cord injury. The current proposal aims to genetically manipulate human embryonic stem cells, study their potential to integrate into immature and mature central nervous system and analyze the effect of genes on such integration. Achieving genetic modification of hESCs will expedite studies with hESCs to cure a variety of human diseases and injuries including spinal cord injury. Our studies will pave the way for discoveries that might lead to novel treatment strategies for spinal cord injury and other neurological conditions. Effective treatments promoting functional repair will significantly increase personal independence for people with spinal cord injury, increase earning capacity and financial independence, and thus decrease the financial burden for the State of California. More importantly, treatments that enhance functional recovery will improve the quality of life for those who are directly or indirectly affected by spinal cord injuries.
Progress Report: 
  • A main goal of research in our laboratory is to identify strategies to promote neural repair in spinal cord injury and related neurological conditions. On the one hand, we have been using mouse models of spinal cord injury to study a long-standing puzzle in the field, namely, why axons, the fibers that connect nerve cells, do not regenerate after injury to the brain and the spinal cord. On the other hand, relevant to this CIRM SEED grant, we have started to explore the developmental and therapeutic potential of human embryonic stem cells (hESCs) for neural repair. We do this by first developing a method to genetically manipulate a HUES line of hESCs. The advent of hESCs has offered enormous potential for regenerative medicine and for basic understanding of human biology. To attain the full potential of hESCs as a tool both for therapeutic development and for basic research, we need to greatly enhance and expand our ability to genetically manipulate hESCs. A major goal for our SEED grant-sponsored research is to establish methods to genetically manipulate the HUES series of hESC lines, which are gaining wide utility in the research community due to the advantages on their growth characteristics over previously developed hESC lines. The first gene that we targeted in HUES cells, Fezf2, is critical for the development of the corticospinal tract, which plays important roles in fine motor control in humans and hence represents an important target for recovery and repair after spinal cord injury. By introducing a fluorescent reporter to the Fezf2 locus, we are now able to monitor the differentiation of hESCs into Fezf2-expressing neuronal lineages. This work has been published. A second goal is to start to explore the developmental and therapeutic potential of these cells and cells that derived from these cells in the brain and spinal cord. We are currently utilizing the cell line genetically engineered above to develop an efficient method to differentiate HUES cells into subcerebral neurons. Results so far have been encouraging. Efforts are also underway to overexpress Fezf2 as a complementary approach to drive the differentiation of HUES cells into specific neuronal types. Together, these studies will lay down the foundation for therapeutic development with HUES cells and their more differentiated derivatives for neurological disorders including spinal cord injury where neural regeneration can be beneficial. The CIRM SEED grant has allowed us to pursue a new, exciting path of research that we would have not pursued had we not been awarded the grant. Furthermore, the CIRM funded research has opened a new window of opportunity for us to explore genetic engineering of hESCs to model human neurological conditions in future.

Modeling Parkinson's Disease Using Human Embryonic Stem Cells

Funding Type: 
SEED Grant
Grant Number: 
RS1-00331
ICOC Funds Committed: 
$758 999
Disease Focus: 
Parkinson's Disease
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
Cell Line Generation: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 
Parkinson’s disease (PD) is the most frequent neurodegenerative movement disorder caused by damage of dopamine-producing nerve cells (DA neuron) in patient brain. The main symptoms of PD are age-dependent tremors (shakiness). There is no cure for PD despite administration of levodopa can help to control symptoms. Most of PD cases are sporadic in the general population. However, about 10-15% of PD cases show familial history. Genetic studies of familial cases resulted in identification of PD-linked gene changes, namely mutations, in six different genes, including α-synuclein, LRRK2, uchL1, parkin, PINK1, and DJ-1. Nevertheless, it is not known how abnormality in these genes cause PD. Our long-term research goal is to understand PD pathogenesis at cellular and molecular levels via studying functions of these PD-linked genes and dysfunction of their disease-associated genetic variants. A proper experimental model plays critical roles in defining pathogenic mechanisms of diseases and for developing therapy. A number of cellular and animal models have been developed for PD research. Nevertheless, a model closely resembling generation processes of human DA nerve cells is not available because human neurons are unable to continuously propagate in culture. Nevertheless, human embryonic stem cells (hESCs) provide an opportunity to fulfill the task. hESCs can grow and be programmed to generate DA nerve cells. In this study, we propose to create a PD model using hESCs. The strategy is to express PD pathogenic mutants of α-synuclein or LRRK2 genes in hESCs. Mutations in α-synuclein or LRRK2 genes cause both familial and sporadic PD. α-Synuclein is a major component of Lewy body, aggregates found in the PD brain. The model will allow us to determine molecular action of PD pathogenic α-synuclein and LRRK2 mutants during generation of human DA neuron and interactions of PD related genes and environmental toxins in DA neurons derived from hESCs. Our working hypothesis is that PD associated genes function in hESCs-derived DA neurons as in human brain DA neurons. Pathogenic mutations in combination with environmental factors (i.e. aging and oxidative stress) impair hESCs-derived DA function resulting in eventual selective neuronal death. In this study, we will firstly generate PD cellular models via expressing two PD-pathogenic genes, α-synuclein and LRRK2 in hESCs. We will next determine effects of α-synuclein and LRRK2 on hESCs and neurons derived from these cells. Finally, we will determine whether PD-causing toxins (i.e. MPP+, paraquat, and rotenone) selectively target to DA neurons derived from hESCs. Successful completion of this study will allow us to study the pathological mechanism of PD and to design strategies to treat the disease.
Statement of Benefit to California: 
Parkinson’s disease (PD) is the second leading neurodegenerative disease with no cure currently available. Compared to other states, California is among one of the states with the highest incidence of this particular disease. First, California growers use approximately 250 million pounds of pesticides annually, about a quarter of all pesticides used in the US (Cal Pesticide use reporting system). A commonly used herbicide, paraquat, has been shown to induce parkinsonism in both animals and human. Other pesticides are also proposed as potential causative agents for PD. Studies have shown increased PD-caused mortality is agricultural pesticide-use counties in comparison to those non-use counties in California. Second, California has the largest Hispanic population. Studies suggest that incidence of PD is the highest among Hispanics (Van Den Eeden et al, American Journal of Epidemiology, Vol. 157, pages 1015-1022, 2003). Thus, finding effective treatments of PD will significantly benefit citizen in California.
Progress Report: 
  • Parkinson’s disease (PD) is the most frequent neurodegenerative movement disorder caused by damage of dopamine-producing nerve cells (DA neuron) in patient brain. The main symptoms of PD are age-dependent tremors (shakiness). There is no cure for PD despite administration of levodopa can help to control symptoms.

  • Most of PD cases are sporadic in the general population. However, about 10-15% of PD cases show familial history. Genetic studies of familial cases resulted in identification of PD-linked gene changes, namely mutations, in six different genes, including α-synuclein, LRRK2, uchL1, parkin, PINK1, and DJ-1. Nevertheless, it is not known how abnormality in these genes cause PD. Our long-term research goal is to understand PD pathogenesis at cellular and molecular levels via studying functions of these PD-linked genes and dysfunction of their disease-associated genetic variants.

  • A proper experimental model plays critical roles in defining pathogenic mechanisms of diseases and for developing therapy. A number of cellular and animal models have been developed for PD research. Nevertheless, a model closely resembling generation processes of human DA nerve cells is not available because human neurons are unable to continuously propagate in culture. Nevertheless, human embryonic stem cells (hESCs) provide an opportunity to fulfill the task. hESCs can grow and be programmed to generate DA nerve cells. In this study, we propose to create a PD model using hESCs.

  • During the funding period, we have generated a number of human ES cell lines overexpressing α-synuclein and two disease-associated α-synuclein mutants. These cells are being used to determine the cellular and molecular effects of the disease genes on human ES cells and the PD affected dopaminergic neurons made from these cells. We have found that normal and disease α-synucleins have little effect on hESC growth and differentiation. We will continue to investigate roles of this protein in modulating PD affected dopaminergic neurons. Completion of this study will allow us to study the pathological mechanism of PD and to design strategies to treat the disease.

Gene regulatory mechanisms that control spinal neuron differentiation from hES cells.

Funding Type: 
SEED Grant
Grant Number: 
RS1-00288
ICOC Funds Committed: 
$807 749
Disease Focus: 
Amyotrophic Lateral Sclerosis
Neurological Disorders
Spinal Muscular Atrophy
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 
More than 600 disorders afflict the nervous system. Common disorders such as stroke, epilepsy, Parkinson’s disease and autism are well-known. Many other neurological disorders are rare, known only to the patients and families affected, their doctors and scientists who look to rare disorders for clues to a general understanding of the brain as well as for treatments for specific diseases. Neurological disorders strike an estimated 50 million Americans each year, exacting an incalculable personal toll and an annual economic cost of hundreds of billions of dollars in medical expenses and lost productivity. There are many potential applications for using human embryonic stem (hES) cells to treat neurological diseases and injuries; however, a critical barrier to progress in the field is the ability to efficiently and reliably control neuronal differentiation from these cells. The main goal of this proposal is to define the gene regulatory mechanisms that control the acquisition of neuronal fate from hES cells. Longer term, we plan to produce small compounds (drugs) that greatly facilitate this process. Drugs that enhance neuron formation are likely to improve scientists’ ability to manipulate hES cells and create in vitro models for studying neurological diseases. Most importantly, drugs of this type may stimulate endogenous stem cells within adults to self-repair damaged areas of the brain. Because so little is known about how hES cells differentiate into neurons at the molecular level, this grant will focus on understanding how a single neuronal subtype is generated – motor neurons. Why motor neurons? Motor neuron diseases are a group of progressive neurological disorders that destroy cells that control essential muscle activity such as speaking, walking, breathing and swallowing. Eventually, the ability to control voluntary movement can be lost. Motor neuron diseases may be inherited or acquired, and they occur in all age groups. In adults, symptoms often appear after age 40. In children, particularly in inherited or familial forms of the disease, symptoms can be present at birth or appear before the child learns to walk. Is there a treatment? There is no cure or standard treatment for motor neuron diseases. Prognosis varies depending on the type of motor neuron disease and the age of onset; however, many types such as ALS and some forms of spinal muscular atrophy are typically fatal.The experiments in this proposal seek to understand mechanisms that will be directly applicable to hES cells and their use for treating motor neuron diseases. Moreover, the mechanisms controlly motor neuron formation are also likely to be relevant to many other neuronal subtypes. Therefore, these studies should provide essential and general insight into medically deploying strategies for converting hES cells into specific neuronal subtypes and thereby serve as a platform for treating a wide range of neurological diseases.
Statement of Benefit to California: 
The long term goal of this research grant proposal is to understand and treat diseases and injuries of the nervous system using hES cells. Neurological disorders such as stroke, epilepsy, Parkinson’s disease and autism strike an estimated 5 million Californians each year, exacting an incalculable personal toll and an annual economic cost of billions of dollars in medical expenses and lost productivity. Thus, one benefit that will be derived from this area of research is the generation of specific tools and methods for reducing medical costs and increasing the quality of life and level of productivity of afflicted Californians. A second key benefit derived from this research grant proposal is the training of new scientists to serve as educators and researchers for the future, many in the burgeoning area of stem cell biology for which the State of California has emerged as a world’s leader. Finally, the discoveries derived from innovative and multidisciplinary research on hES cells described in this proposal, including the use of chemistry to create drug leads for regulating stem cell differentiation, are likely to lead to important new areas of intellectual property that are essential for creating high quality jobs in the biotechnology and pharmaceutical industries in California.
Progress Report: 
  • The differentiation of stem cells into clinically-useful cell types is directly dependent on the accurate regulation of gene activation/repression. During the last scientific period we have focused our research on aim 2 of the grant proposal -– to characterize enzymes that are recruited to DNA for the regulation of genes. This effort has employed new DNA sequencing technologies to understand how the lysine specific demethylase (KDM1, LSD1) control gene expression in embryonic stem cells.

Optimization of guidance response in human embryonic stem cell derived midbrain dopaminergic neurons in development and disease

Funding Type: 
SEED Grant
Grant Number: 
RS1-00271
ICOC Funds Committed: 
$633 170
Disease Focus: 
Parkinson's Disease
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 
A promising approach to alleviating the symptoms of Parkinson’s disease is to transplant healthy dopaminergic neurons into the brains of these patients. Due to the large number of transplant neurons required for each patient and the difficulty in obtaining these neurons from human tissue, the most viable transplantation strategy will utilize not fetal dopaminergic neurons but dopaminergic neurons derived from human stem cell lines. While transplantation has been promising, it has had limited success, in part due to the ability of the new neurons to find their correct targets in the brain. This incorrect targeting may be due to the lack of appropriate growth and guidance cues as well as to inflammation in the brain that occurs in response to transplantation, or to a combination of the two. Cytokines released upon inflammation can affect the ability of the new neurons to connect, and thus ultimately will affect their biological function. In out laboratory we have had ongoing efforts to determine the which guidance molecules are required for proper targeting of dopaminergic neurons during normal development and we have identified necessary cues. We now plan to extend these studies to determine how these critical guidance cues affect human stem cell derived dopaminergic neurons, the cells that will be used in transplantation. In addition, we will examine how these guidance cues affect both normal and stem cell derived dopaminergic neurons under conditions that are similar to the diseased and transplanted brain, specifically when the brain is inflamed. Ultimately, an understanding of how the environment of the transplanted brain influences the ability of the healthy new neurons to connect to their correct targets will lead to genetic, and/or drug-based strategies for optimizing transplantation therapy.
Statement of Benefit to California: 
The goal of our work is to further optimize our ability to turn undifferentiated human stem cells into differentiated neurons that the brain can use as replacement for neurons damaged by disease. We focus onParkinson’s disease, a neurodegenerative disease that afflicts 4-6 million people worldwide in all geographical locations, but which is more common in rural farm communities compared to urban areas (Van Den Eeden et al., 2003), a criteria important for California’s large farming population. In Parkinson’s patients, a small, well-defined subset of neurons, the midbrain dopaminergic neurons have died, and one therapeutic strategy is to transplant healthy replacement neurons to the patient. Our work will further our understanding of the biology of these neurons in normal animals. This will allow us to refine the process of turning human ES cells onto biologically active dopaminergic neurons that can be used in transplantation therapy. Our work will be of benefit to all Parkinson’s patients including afflicted Californians. In addition to the direct benefit in improving PD therapies, discoveries from this work are also likely to generate substantial intellectual property and further boost clinical and biotechnical development efforts in California.
Progress Report: 
  • A promising approach to alleviating the symptoms of Parkinson's disease is to transplant healthy dopaminergic neurons into the brains of these patients. Due to the large number of transplant neurons required for each patient and the difficulty in obtaining these neurons from human tissue, the most viable transplantation strategy will utilize not fetal dopaminergic neurons but dopaminergic neurons derived from human stem cell lines. While transplantation has been promising, it has had limited success, in part due to the ability of the new neurons to find their correct targets in the brain. This incorrect targeting may be due to the lack of appropriate growth and guidance cues as well as to inflammation in the brain that occurs in response to transplantation, or to a combination of the two. Cytokines released upon inflammation can affect the ability of the new neurons to connect, and thus ultimately will affect their biological function. In out laboratory we have been examining which guidance molecules are required for proper targeting of dopaminergic neurons during normal development and have identified necessary cues. We have now extended these studies to determine that two of the molecules have dramitc effects on dopaminergic neurons made from human embryonic stem cellls and that at least in vitro, cytokines do not mask these effects. Ultimately, an understanding of how the environment of the transplanted brain influences the ability of the healthy new neurons to connect to their correct targets will lead to genetic, and/or drug-based strategies for optimizing transplantation therapy.

Development of human ES cell lines as a model system for Alzheimer disease drug discovery

Funding Type: 
SEED Grant
Grant Number: 
RS1-00247
ICOC Funds Committed: 
$492 750
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
Cell Line Generation: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 
Alzheimer disease (AD) is a progressive neurodegenerative disorder that currently affects over 4.5 million Americans. By the middle of the century, the prevalence of AD in the USA is projected to almost quadruple. As current therapies do not abate the underlying disease process, it is very likely that AD will continue to be a clinical, social, and economic burden. Progress has been made in our understanding of AD pathogenesis by studying transgenic mouse models of the disease and by utilizing primary neuronal cell cultures derived from rodents. However, key proteins that are critical to the pathogenesis of this disease exhibit many species-specific differences at both a biophysical and functional level. Additional species differences in other as yet unidentified AD-related proteins are likely to also exist. Thus, there is an urgent need to develop novel models of AD that recapitulate the complex array of human proteins involved in this disease. Cell culture-based models that allow for rapid high-throughput screening and the identification of novel compounds and drug targets are also critically needed. To that end we propose to model both sporadic and familial forms of AD by generating two novel human embryonic stem cell lines (hES cells). Differentiation of these lines along a neuronal lineage will provide researchers with an easily accessible and reproducible neuronal cell culture model of AD. These cells will also allow high-throughput screening and experimentation in neuronal cells with a species-relevant complement of human proteins. In Aim 1 we will develop and characterize hES cell lines designed to model both sporadic and familial forms of AD. To model sporadic AD we will stably transfect HUES7 hES cells (developed by Douglas Melton) with lentiviral constructs coding for human wild type amyloid precursor protein (APP-695) under control of the human APP promoter. APP is well expressed within hES cells and upregulated upon neuronal differentiation. To model familial AD and generate cells that exhibit a more aggressive formation of oligomeric A species we will also develop a second hES cell line stably transfected with human APP that includes the Arctic (E693G) mutation.In Aim 2 we will utilize our wild-type APP hES cells to perform a high-throughput siRNA screen. We will utilize AMAXA reverse-nucleofection in conjunction with a human druggable genome siRNA array (Dharmacon) that targets 7309 genes considered to be potential therapeutic targets. Following transfection conditioned media will be examined by a sensitive ELISA to identify novel targets that modulate A levels. In addition a Thioflavin S assay will determine any effects on A aggregation. Follow-up experiments will confirm promising candidates identified in the high-throughput screen. Taken together these studies aim to establish novel AD-specific hES cell lines and identify promising new therapeutic targets for this devastating disease.
Statement of Benefit to California: 
Alzheimer disease (AD) is a progressive neurodegenerative disorder that currently affects over 500 thousand Californians. As the baby-boomer generation ages the prevalence of AD in California is projected to almost quadruple such that 1 in every 45 individuals will be afflicted. As current therapies do not abate the underlying disease process, it is very likely that AD will continue to be a major clinical, social, and economic burden. Some estimates have even suggested that AD alone may bankrupt the current Californian health care system. Progress has been made in our understanding of AD by studying rodent-based models of the disease. However, key proteins that are critical to the disease exhibit many species-specific differences at both a biophysical and functional level. Thus, there is an urgent need to develop novel models of AD that exhibit the complex array of human proteins involved in this disease. Cell culture-based models that also allow for rapid high-throughput screening and the identification of novel compounds and drug targets are also in critical need. The proposed studies aim to utilize human embryonic stem (hES) cells to establish a novel cell culture based model of Alzheimer’s disease. Once developed these cells will provide Californian researchers with a unique tool to investigate genes and proteins that influence the progress of AD. In this proposal we will also utilize these hES cells to perform a high-throughput screen of over 7300 genes to identify multiple novel drug targets that may critically regulate the development of this disease. Taken together these studies aim to establish novel AD-specific hES cell lines that can be utilized by multiple Californian researchers to identify promising new therapeutic targets for this devastating disease.
Progress Report: 
  • Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder. It is characterized by an irreversible loss of neurons accompanied by the accumulation of extracellular amyloid plaques and intraneuronal neurofibrillary tangles. Currently, 5.3 million Americans are afflicted with this insidious disorder, including over 588,000 in the State of California alone. Mouse models of AD have contributed significantly to our understanding of the proteins and factors involved in the pathology of AD. However, there are critical differences between mouse and human cell physiology that likely dramatically influence the development of AD-related pathologies. Hence, there is an urgent need to develop novel human neuronal cell-based models of AD.
  • To achieve this goal, we have generated stable human embryonic stem cell (hES) lines over-expressing the gene for human amyloid precursor protein (APP). We succeeded in creating several lines of hES cells that stably express either wild-type (unaltered) APP or APP that includes rare familial mutations known to cause early-onset cases of AD. In each line, transgene expression is driven under control of the human APP proximal promoter. Mutant versions of APP utilized include the “Swedish” mutation which increases production of Aß and the “Arctic” mutation which increases the assembly and accumulation of synaptotoxic Aß oligomers and protofibrils. The generation of lines that harbor familial mutations in APP both provides an aggressive model of AD, to facilitate the identification of targets that modulate not only Aß production but also the assembly of toxic oligomeric species.
  • In addition to generating stable HUES7 and H9 cell lines over-expressing mutant and wild type forms of APP, we also succeeded in establishing a neuronal differentiation protocol which results in 80% of cells adopting a mature neuronal fate. Importantly, we have also verified by biochemical measures that APP-overexpressing cells produce significantly elevated levels of Aß. As a result we are now preparing to utilize these novel cell lines to identify and examine genes that regulate Aß production and hence the development of AD.
  • Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder. Currently, 5.3 million individuals are afflicted with this insidious disorder, including over 588,000 in the State of California alone. Unfortunately, existing therapies provide only palliative relief. Although transgenic mouse models and cell culture experiments have contributed significantly to our understanding of the proteins and factors involved in the pathology of AD, these approaches are beset by certain critical limitations. Most notably, mouse models by definition are not based on human cells and cell culture models have been limited to non-human or non-neuronal cells. Hence, there is an urgent need to develop a human neuronal cell-based model of AD. To address this need, we have engineered human embryonic stem cell lines to overexpress mutant human genes that cause early-onset familial AD. These novel stem cell lines will provide a valuable system to test therapies and enhance our understanding of the mechanisms that mediate this devastating disease. Interestingly, we have found that overexpression of these AD-related genes can trigger the rapid differentiation of human embryonic stem cells into neuronal cells. We have examined the mechanisms involved and anticipate that our findings may provide a novel and rapid method to generate neurons from embryonic stem cells.

New Chemokine-Derived Therapeutics Targeting Stem Cell Migration

Funding Type: 
SEED Grant
Grant Number: 
RS1-00225
ICOC Funds Committed: 
$759 000
Disease Focus: 
Spinal Cord Injury
Neurological Disorders
Stroke
Trauma
Stem Cell Use: 
Adult Stem Cell
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 
This proposal describes a sharply-focused, timely, and rigorous effort to develop new therapies for the treatment of injuries of the Central Nervous System (CNS). The underlying hypothesis for this proposal is that chemokines and their receptors (particularly those involved in inflammatory cascades) actually play important roles in mediating the directed migration of human neural stem cells (hNSCs) to, as well as engagement and interaction with, sites of CNS injury, and that understanding and manipulating the molecular mechanism of chemokine-mediated stem cell homing and engagement will lead to new, better targeted, more specific, and more efficacious chemokine-mediated stem cell-based repair strategies for CNS injury. In recent preliminary studies, we have discovered and demonstrated the important role of chemokine SDF-1-alpha and its receptor CXCR4 in mediating the directed migration of hNSCs to sites of CNS injury. To manipulate this SDF-1-alpha/CXCR4 pathway in stem cell migration, we have developed Synthetically and Modularly Modified Chemokines (SMM-chemokines) as highly potent and specific therapeutic leads. Here in this renewal application we propose to extend our research into a new area of stem cell biology and medicine involving chemokine receptors such as CXCR4 and its ligand SDF-1. Specifically, we will design more potent and specific analogs of SDF-1-alpha to direct the migration of beneficial stem cells toward the injury sites for the repair process.
Statement of Benefit to California: 
This proposal describes a sharply-focused, timely, and rigorous effort to develop new therapies for the treatment of injuries of the Central Nervous System (CNS). CNS injuries and related disorders such as stroke, traumatic brain injury and spinal cord injury are significant health issues in the nation including the state of California. The new stem cell-based therapies to be developed from this application will have important clinical application in patients with these diseases in California.
Progress Report: 
  • Human neural stem cells (hNSCs) expressing CXCR4 have been found to migrate in vivo toward an infarcted area that are representative of central nervous system (CNS) injuries, where local reactive astrocytes and vascular endothelium up-regulate the SDF-1α secretion level and generate a concentration gradient. Exposure of hNSCs to SDF-1α and the consequent induction of CXCR4-mediated signaling triggers a series of intracellular processes associated with fundamental aspects of survival, proliferation and more importantly, proper lamination and migration during the early stages of brain development [1]. To date, there is no crystal structure available for chemokine receptors [2, 3]. Structural and modeling studies of SDF-1α and D-(1~10)-L-(11~69)-vMIP-II in complexes with CXCR4 TM helical regions led us to a plausible “two-pocket” model for CXCR4 interaction with agonists or antagonists. [4-6] In this study, we extended the employment of this model into the novel design strategy for highly potent and selective CXCR4 agonist molecules, with potentials in activating CXCR4-mediated hNSC migration by mimicking a benign version of the proinflamatory signal triggered by SDF-1α. Successful verification of directed, extensive migration of hNSCs, both in vitro and in transplanted uninjured adult mouse brains, with the latter manifesting significant advantages over the natural CXCR4 agonist SDF-1α in terms of both distribution and stability in mouse brains, strongly supports the effectiveness and high potentials of these de novo designed CXCR4 agonist molecules in optimizing directed migration of transplanted human stem cells during the reparative therapeutics for a broad range of neurodegenerative diseases in a more foreseeable future.
  • Our final progress report is divided into 3 subsections, each addressing progress in the 3 fundamental areas of investigation for the successful completion of this project:
  • (1) De-novo design and synthesis of CXCR4-specific SDF-1α analogs.
  • (2) In vitro studies on validating biological potencies of molecules in (1) in activating CXCR4 down-stream signaling.
  • (3) In vivo studies on migration of transplanted neural precursor cells (NPCs) in co-administration of molecules with validated biological activities in (2).

Identifying small molecules that stimulate the differentiation of hESCs into dopamine-producing neurons

Funding Type: 
SEED Grant
Grant Number: 
RS1-00215
ICOC Funds Committed: 
$564 309
Disease Focus: 
Parkinson's Disease
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 
In this application, we propose to identify small molecule compounds that can stimulate human embryonic stem cells to become dopamine-producing neurons. These neurons degenerate in Parkinson’s disease, and currently have very limited availability, thus hindering the cell replacement therapy for treating Parkinson’s disease. Our proposed research, if successful, will lead to the identification of small molecule compounds that can not only stimulate cultured human embryonic stem cells to become DA neurons, but may also stimulate endogenous brain stem cells to regenerate, since the small molecule compounds can be made readily available to the brain due to their ability to cross the blood-brain barrier. In addition, these small molecule compounds may serve as important research tools, which can tell us the fundamental biology of the human embryonic stem cells.
Statement of Benefit to California: 
The proposed research will potentially lead to a cure for the devastating neurodegenerative, movement disorder, Parkinson’s disease. The proposed research will potentially provide important research tools to better understand hESCs. Such improved understanding of hESCs may lead to better treatments for a variety of diseases, in which a stem-cell based therapy could make a difference.
Progress Report: 
  • Parkinson’s disease is the most common movement disorder due to the degeneration of brain dopaminergic neurons. One strategy to combat the disease is to replenish these neurons in the patients, either through transplantation of stem cell-derived dopaminergic neurons, or through promoting endogenous dopaminergic neuronal production or survival. We have carried out a small molecule based screen to identify compounds that can affect the development and survival of dopaminergic neurons from pluripotent stem cells. The small molecules that we have identified will not only serve as important research tools for understanding dopaminergic neuron development and survival, but potentially could also lead to therapeutics in the induction of dopaminergic neurons for treating Parkinson’s disease.

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