Huntington’s disease (HD) is a devastating degenerative brain disease with a 1 in 10,000 risk of having a mutation that inevitably leads to death. These numbers do not fully reflect the large societal and familial cost of HD, which requires extensive caregiving. HD has no effective treatment or cure and symptoms progress without stopping for 15-20 years, with onset typically striking in midlife. Because HD is genetically dominant, the disease has a 50% chance of being inherited by the children of patients. Symptoms of the disease include uncontrolled movements, difficulties in carrying out daily tasks or continuing employment, and severe psychiatric manifestations including depression. Specific regions of the brain are severely affected, most notably the striatum. Current treatments only treat some symptoms and do not change the course of the disease, therefore a completely unmet medical need exists. Human embryonic stem cells (hESCs) offer a possible long-term treatment that could relieve the tremendous suffering experienced by patients and their families. HD is the 3rd most prevalent neurodegenerative disease, but because it is entirely genetic and the mutation known, a diagnosis can be made with certainty and clinical applications of hESCs may provide insights into treating brain diseases that are not caused by a single, known mutation. Trials in mice where protective factors were directly delivered to the brains of HD mice have been effective, suggesting that delivery of these factors by hESCs may help patients. In addition, transplantation of fetal brain tissue in HD patients suggests that replacing neurons that are lost may also be effective. While encouraging, the ability to differentiate hESCs into neuronal populations offers a powerful and sustainable alternative for cell replacement. Further, hESCs offer an opportunity to create cell models in which to identify earlier markers of disease onset and progression and for drug development.
A core group of HD and stem cell experts together with clinicians experienced in stem cell and HD clinical trials have been assembled by the PI to initiate the planning process for a hESC-based therapeutic trial for HD within four years. While feasible, in order for the potential of hESCs in HD to be realized, a very forward thinking disease team effort will allow the most experienced investigators in HD, stem cell research and clinical trials to come together and determine the best way to treat the disease. This planning grant would allow for these interactions to occur in a structured and consistent manner. The planning award will be used to identify critical gaps in our knowledge, available technology, and areas of expertise that need to be addressed prior to moving hESC-based therapy for HD into the clinic. Because the work proposed would entail the use of non-NIH approved hES cell lines, it would be ineligible for Federal funding.
The disability and loss of earning power and personal freedom resulting from Huntington's disease (HD) is devastating and creates a financial burden for California. Individuals are struck in the prime of life, at a point when they are their most productive and have their highest earning potential. Further, as the disease progressives, individuals require institutional care facilities at great financial cost. Therapies using human embryonic stem cells (hESCs) have the potential to change the lives of hundreds of individuals and their families, which brings the human cost into the thousands. Further, hESCs from HD patients will help us understand the factors that dictate the course of the disease and provide a resource for drug development. For the potential of hESCs in HD to be realized, a very forward thinking disease team effort will allow the most experienced investigators in HD and stem cell research and clinical trials to come together and determine the best way to treat the disease. This planning grant would allow for these interactions to occur in a structured and consistent manner. California researchers need the resources needed to allow researchers having the necessary expertise and technologies to come together as a team to develop hESCs into viable treatments. The federal constraints on hESCs create a critical need for the development of treatments using hESCs supported and staffed with non-federal funds.
We have assembled a strong core team of California-based senior investigators to plan goals and strategies for taking hESCs from the lab to the clinic. The planning award will be used to identify critical gaps in our knowledge, available technology, and areas of expertise that need to be addressed prior to moving SC-based therapy for HD into the clinic. We will also put in place critical milestones to be met and to formalize a management plan that will ensure that the milestones are achieved. We will build on existing regional stem cell resources used by scientists from California institutions. Anticipated benefits to the citizens of California include: 1) development of new cell-based treatments for Huntington's disease with application to other neurodegenerative diseases such as Alzheimer's and Parkinson's diseases that affect thousands of individuals in California; 2) improved methods for following the course of the disease in order to treat HD as early as possible before symptoms are manifest; 3) development of intellectual property that could form the basis of new biotech startup companies; and 4) improved methods for drug development that could directly benefit citizens of the state. With the proposed disease team our vision of bringing treatments for HD and other neurodegenerative diseases to the clinic can become a reality.
Motor neuron (MN) diseases such as spinal muscular atrophy and amyotrophic lateral sclerosis lead to progressive degeneration of MNs, presenting first with muscle weakness, followed by locomotor defects and frequently death due to respiratory failure. While progress has been made in identifying genes associated with MN degeneration, the molecular and cellular processes underlying disease onset and progression remain unclear, and no effective therapies are available. Methods to direct the development of normal and diseased motor neurons from human embryonic and induced pluripotent stem cells have recently been developed, raising hope that these cells could offer a means for investigating the root causes of MN disease and devising screens for neuroprotective agents. Most stem cell-based disease modeling efforts have thus far focused on the issue of MN survival at the end stages of disease progression. However, studies in animal models and human patients indicate that MN function declines well before MN death is prevalent. We have developed a simple, yet physiologically relevant platform for measuring the activity of normal and diseased human MNs and muscle cells in a manner that has not previously been possible. Here we propose to explore how MN function declines; eventually we hope to test new therapeutics. These studies provide a crucial bridge between studies of motor circuit function in animal models and the molecular and cellular tools available to study cells in culture.
Neurological diseases are among the most debilitating medical conditions that affect millions of Californians each year, and many more worldwide. Few effective treatments for these diseases currently exist, in part because we know very little about the mechanisms underlying these conditions. Through the use of human embryonic stem cell and induced pluripotent stem cell technologies, it is now possible to create neurons from patients suffering from a variety of neurological disorders that can serve as the basis for cell culture-based models to study disease pathologies. Our proposed research specifically seeks to develop an innovative system for investigating the early stages of neuromuscular disease onset and progression in an experimentally accessible cell culture setting. The generation of this model will constitute an important step towards understanding the root cause of neurological dysfunction and developing a platform for the discovery of drugs that can alter disease outcomes and improve the productivity and quality of life for many Californians. Moreover, progress in this field will help solidify the leadership role of California in bringing stem cell research to the clinic, and stimulate the future growth of the biotechnology and pharmaceutical industries within the state.
Stem cell therapy holds promise for the almost million Americans yearly who suffer a stroke. Preclinical data have shown that human neural stem cells (hNSCs) aid recovery after stroke, resulting in a major effort to advance stem cell therapy to the clinic, and we are currently transitioning our hNSC product to the clinic for stroke therapy. In this proposal we will explore how these cells improve lost function. We have already shown that injected hNSCs secrete factors that promote the gross rewiring of the brain, a major component of the spontaneous recovery observed after stroke. We now intend to focus on the connections between neurons, the synapses, which are a critical part of this rewiring process. We aim to quantify the effect of hNSCs on synapse density and function, and explore whether the stem cells secrete restorative synaptogenic factors or form functional synapses with pre-existing neurons. Our pursuit is made possible by our combination of state-of-the-art imaging techniques enabling us to visualize, characterize, and quantify these tiny synaptic structures and their interaction with the hNSCs. Furthermore, by engineering the hNSCs we can identify the factors they secrete in the brain and identify those which modulate synaptic connections. Our proposed studies will provide important insight into how transplanted stem cells induce recovery after stroke, with potential applicability to other brain diseases.
Cerebrovascular stroke is the fourth leading cause of mortality in the United States and a significant source of long-term physical and cognitive disability that has devastating consequences to patients and their families. In California alone, over 9% of adults 65 years or older have had a stroke according to a 2005 study. In the next 20 years the societal toll is projected to amount to millions of patients and 18.8 billion dollars per year in direct medical costs. To date, there is no approved therapeutic agent for the recovery phase after stroke, making the long-term care of stroke patients a tremendous socioeconomic burden that will continue to rise as our aging population increases. Our laboratory and others have demonstrated the promise of stem cell transplantation to treat stroke. We are dedicated to developing human neural stem cells (hNSCs) as a novel neuro-restorative treatment for lost motor function after stroke. The goal of our proposed work is to further understand how transplanted hNSCs improve stroke recovery, as dissecting the mechanism of action of stem cells in the stroke brain will ultimately improve the chance of clinical success. This could potentially provide significant cost savings to California, but more importantly benefit the thousands of Californians and their families who struggle with the aftermath of stroke.
Our goal is to use the mechanisms that generate neuronal networks to create neurons from stem cells, to either replace diseased and damaged tissue or as a source of material to study disease mechanisms. A key focus of such regenerative studies is to restore function to the spinal cord, which is particularly vulnerable to damage. However, although considerable progress has been made in understanding how to direct stem cells towards motor neurons that control coordinated movement, little progress has been made so far directing stem cells to form the sensory neurons that allow us to experience the environment around us.
Our proposed research will use insights from the mechanisms known to generate the sensory neurons during the development of the spinal cord, to derive these neurons from stem cells. We will initially use mouse embryonic stem cells in these studies, to accelerate the experimental progress. We will then apply our findings to human embryonic stem cells, and assess whether these cells are competent to repopulate the spinal cord. These studies will significantly advance our understanding of how to generate the full repertoire of neural subtypes necessary to repair the spinal cord after injury, specifically permitting patients to recover sensations such as pain and temperature. Moreover, they also represent a source of therapeutically beneficial cells for modeling debilitating diseases, such as the chronic insensitivity to pain.
Millions of Californians live with compromised nervous systems, damaged by either traumatic injury or disease. These conditions can be devastating, stripping patients of their ability to move, feel and think, and currently have no cure. As well as being debilitating for patients, living with these diseases is also extremely expensive, costing both Californians and the state of California many billions of dollars. For example, the estimated lifetime cost for a single individual managing spinal paralysis is estimated to be up to $3 million.
Stem cell technology offers tremendous hope for reversing or ameliorating both disease and injury states. Stem cells can be used to replenish any tissue damaged by injury or disease, including the spinal cord, which is particularly vulnerable to physical damage. Our proposed studies will develop the means to produce the spinal sensory neurons that permit us to perceive the environment. We will also determine whether these in vitro derived sensory neurons are suitable for transplantation back into the spinal cord. The generation of these neurons will constitute an important step towards reversing or ameliorating spinal injuries, and thereby improve the productivity and quality of life of many Californians. Moreover, progress in this field will solidify the leadership role of California in stem cell research and stimulate the future growth of the biotechnology and pharmaceutical industries within the state.
Stem cells generate mature, functional cells after proteins on the cell surface interact with cues from the environment encountered during development or after transplantation. Thus, these cell surface proteins are critical for directing transplanted stem cells to form appropriate cells to treat injury or disease. A key modification regulating cell surface proteins is glycosylation, which is the addition of sugars onto proteins and has not been well studied in neural stem cells. We focus on a major unsolved problem in the neural stem cell field: do different proteins coated with sugars on the surfaces of cells in this lineage (neuron precursors, NPs and astrocyte precursors, APs) determine what types of mature cells will form? We hypothesize key players directing cellular decisions are glycosylated proteins controlling how precursors respond to extracellular cues. We will address this hypothesis with aims investigating whether (1) glycosylation pathways predicted to affect cell surface proteins differ between NPs and APs, (2) glycosylated proteins on the surface of NPs and APs serve as instructive cues governing fate or merely mark their fate potential, and (3) glycosylation pathways regulate cell surface proteins likely to affect fate choice. By answering these questions we will better understand the formation of NPs and APs, which will improve the use of these cells to treat brain and spinal cord diseases and injuries.
The goal of this project is to determine how cell surface proteins differ between cells in the neural lineage that form two types of final, mature cells (neurons and astrocytes) in the brain and spinal cord. In the course of these studies, we will uncover specific properties of human stem cells that are used to treat neurological diseases and injuries. We expect this knowledge will improve the use of these cells in transplants by enabling more control over what type of mature cell will be formed from transplanted cells. Also, cells that specifically generate either neurons or astrocytes can be used for drug testing, which will help to predict the effects of compounds on cells in the human brain. We hope our research will greatly improve identification, isolation, and utility of specific types of human neural stem cells for treatment of human conditions. Furthermore, this project will generate new jobs for high-skilled workers and, hopefully, intellectual property that will contribute to the economic growth of California.
We propose to elucidate pathways of genes that lead from early causes to later defects in Alzheimer’s Disease (AD), which is common, fatal, and for which no effective disease-modifying drugs are available. Because no effective AD treatment is available or imminent, we propose to discover novel genetic pathways by screening purified human brain cells made from human reprogrammed stem cells (human IPS cells or hIPSC) from patients that have rare and aggressive hereditary forms of AD. We have already discovered that such human brain cells exhibit an unique biochemical behavior that indicates early development of AD in a dish. Thus, we hope to find new drug targets by using the new tools of human stem cells that were previously unavailable. We think that human brain cells in a dish will succeed where animal models and other types of cells have thus far failed.
Alzheimer’s Disease (AD) is a fatal neurodegenerative disease that afflicts millions of Californians. The emotional and financial impact on families and on the state healthcare budget is enormous. This project seeks to find new drug targets to treat this terrible disease. If we are successful our work in the long-term may help diminish the social and familial cost of AD, and lead to establishment of new businesses in California using our approaches.
Parkinson’s disease (PD), is one of the leading causes of disabilities and death and afflicting millions of people worldwide. Effective treatments are desperately needed but the underlying molecular and cellular mechanisms of Parkinson’s destructive path are poorly understood. Mitochondria are cell’s power plants that provide almost all the energy a cell needs. When these cellular power plants are damaged by stressful factors present in aging neurons, they release toxins (reactive oxygen species) to the rest of the neuron that can cause neuronal cell death (neurodegeneration). Healthy cells have an elegant mitochondrial quality control system to clear dysfunctional mitochondria and prevent their resultant devastation. Based on my work that Parkinson’s associated proteins PINK1 and Parkin control mitochondrial transport that might be essential for damaged mitochondrial clearance, I hypothesize that in Parkinson’s mutant neurons mitochondrial quality control is impaired thereby leading to neurodegeneration. I will test this hypothesis in iPSC (inducible pluripotent stem cells) from Parkinson’s patients. This work will be a major step forward in understanding the cellular dysfunctions underlying Parkinson’s etiology, and promise hopes to battle against this overwhelming health danger to our aging population.
Parkinson's disease (PD), one of the most common neurodegenerative diseases, afflicts millions of people worldwide with tremendous global economic and societal burdens. About 500,000 people are currently living with PD in the U.S, and approximate 1/10 of them live in California. The number continues to soar as our population continues to age. An effective treatment is desperately needed but the underlying molecular and cellular mechanisms of PD’s destructive path remain poorly understood. This proposal aims to explore an innovative and critical cellular mechanism that controls mitochondrial transport and clearance via mitophagy in PD pathogenesis with elegant employment of bold and creative approaches to live image mitochondria in iPSC (inducible pluripotent stem cells)-derived dopaminergic neurons from Parkinson’s patients. This study is closely relevant to public health of the state of California and will greatly benefit its citizens, as it will illuminate the pathological causes of PD and provide novel targets for therapuetic intervention.