Neurological Disorders

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

Collection of skin biopsies to prepare fibroblasts from patients with Alzheimer's disease and cognitively healthy elderly controls

Funding Type: 
Tissue Collection for Disease Modeling
Grant Number: 
IT1-06589
ICOC Funds Committed: 
$643 693
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
oldStatus: 
Active
Public Abstract: 
Alzheimer's Disease (AD), the most common form of dementia in the elderly, affects over 5 million Americans. There are no treatments to slow progression or prevent AD. This reflects limitations in knowledge of mechanisms underlying AD, and in tools and models for early development and testing of treatment. Genetic breakthroughs related to early onset AD led to initial treatment targets related to a protein called amyloid, but clinical trials have been negative. Extensive research links genetic risk to AD, even when the age at onset is after the age of 65. AD affects the brain alone, therefore studying authentic nerve cells in the laboratory should provide the clearest insights into mechanisms and targets for treatment. This has recently become feasible due to advances in programming skin cells into stem cells and then growing (differentiating) them into nerve cells. In this project we will obtain skin biopsies from a total of 220 people with AD and 120 controls, who are extensively studied at the UCSD AD Research Center. These studies include detailed genetic (DNA) analysis, which will allow genetic risks to be mapped onto reprogrammed cells. These derived cells that preserve the genetic background of the person who donated the skin biopsy will be made available to the research community, and have the promise to accelerate studies of mechanisms of disease, understanding genetic risk, new treatment targets, and screening of new treatments for this devastating brain disorder.
Statement of Benefit to California: 
The proposed project will provide a unique and valuable research resource, which will be stored and managed in California. This resource will consist of skin cells or similar biological samples, suitable for reprogramming, obtained from well-characterized patients with Alzheimer's Disease and cognitively healthy elderly controls. Its immediate impact will be to benefit CIRM-funded researchers as well as the greater research community, by providing them access to critical tools to study, namely nerve cells that can be grown in a dish (cultured) that retain the genetic background of the skin cell donors. This technology to develop and reprogram cells into nerve cells or other cell types results from breakthroughs in stem cell research, many of which were developed using CIRM funding. Alzheimer's Disease affects over 600,000 Californians, and lacks effective treatment. Research into mechanisms of disease, identifying treatment targets, and screening novel drugs will be greatly improved and accelerated through the availability of the resources developed by this project, which could have a major impact on the heath of Californians. California is home to world class academic and private research institutes, Biotechnology and Pharmaceutical Companies, many of whom are already engaged in AD research. This project could provide them with tools to make research breakthroughs and pioneer the development of novel treatments for AD.

Generation and characterization of high-quality, footprint-free human induced pluripotent stem cell lines from 3,000 donors to investigate multigenic diseases

Funding Type: 
hiPSC Derivation
Grant Number: 
ID1-06557
ICOC Funds Committed: 
$16 000 000
Disease Focus: 
Developmental Disorders
Genetic Disorder
Heart Disease
Infectious Disease
Alzheimer's Disease
Neurological Disorders
Autism
Respiratory Disorders
Vision Loss
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
Induced pluripotent stem cells (iPSCs) have the potential to differentiate to nearly any cells of the body, thereby providing a new paradigm for studying normal and aberrant biological networks in nearly all stages of development. Donor-specific iPSCs and differentiated cells made from them can be used for basic and applied research, for developing better disease models, and for regenerative medicine involving novel cell therapies and tissue engineering platforms. When iPSCs are derived from a disease-carrying donor; the iPSC-derived differentiated cells may show the same disease phenotype as the donor, producing a very valuable cell type as a disease model. To facilitate wider access to large numbers of iPSCs in order to develop cures for polygenic diseases, we will use a an episomal reprogramming system to produce 3 well-characterized iPSC lines from each of 3,000 selected donors. These donors may express traits related to Alzheimer’s disease, autism spectrum disorders, autoimmune diseases, cardiovascular diseases, cerebral palsy, diabetes, or respiratory diseases. The footprint-free iPSCs will be derived from donor peripheral blood or skin biopsies. iPSCs made by this method have been thoroughly tested, routinely grown at large scale, and differentiated to produce cardiomyocytes, neurons, hepatocytes, and endothelial cells. The 9,000 iPSC lines developed in this proposal will be made widely available to stem cell researchers studying these often intractable diseases.
Statement of Benefit to California: 
Induced pluripotent stem cells (iPSCs) offer great promise to the large number of Californians suffering from often intractable polygenic diseases such as Alzheimer’s disease, autism spectrum disorders, autoimmune and cardiovascular diseases, diabetes, and respiratory disease. iPSCs can be generated from numerous adult tissues, including blood or skin, in 4–5 weeks and then differentiated to almost any desired terminal cell type. When iPSCs are derived from a disease-carrying donor, the iPSC-derived differentiated cells may show the same disease phenotype as the donor. In these cases, the cells will be useful for understanding disease biology and for screening drug candidates, and California researchers will benefit from access to a large, genetically diverse iPSC bank. The goal of this project is to reprogram 3,000 tissue samples from patients who have been diagnosed with various complex diseases and from healthy controls. These tissue samples will be used to generate fully characterized, high-quality iPSC lines that will be banked and made readily available to researchers for basic and clinical research. These efforts will ultimately lead to better medicines and/or cellular therapies to treat afflicted Californians. As iPSC research progresses to commercial development and clinical applications, more and more California patients will benefit and a substantial number of new jobs will be created in the state.

Generation and characterization of corticospinal neurons from human embryonic stem cells

Funding Type: 
Basic Biology III
Grant Number: 
RB3-02143
ICOC Funds Committed: 
$1 355 063
Disease Focus: 
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
Cell Line Generation: 
iPS Cell
Public Abstract: 
A major goal of stem cell research is to generate various functional human cell types that can be used to better understand how these cells work and to use them directly in therapies. There are currently no effective treatments, let alone a cure, for many neurological conditions. Two particular devastating neurological conditions, spinal cord injury and amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease) share a common element. That is, in both conditions, the corticospinal motor neurons that control skilled voluntary movement are severely damaged, leading to significant loss of motor control. There has been extensive research on spinal cord injury and ALS in recent years. In the field of spinal cord injury, much effort has been devoted to repairing the damaged nerve paths, but this has turned out to be extremely challenging. The work on ALS, on the other hand, has mostly focused on the spinal motor neurons (often referred to as the lower motor neurons in the context of ALS). Our proposed study focuses on the corticospinal motor neurons (or the upper motor neurons) and, more broadly, the subcerebral projection neurons. Taking clues from studies in mice, we aim to understand how the subcerebral projection neurons including the corticospinal motor neurons can be made from human embryonic stem cells. We will focus on the later steps in differentiation that are not well understood, which gave rise to different types of neurons in the cerebral cortex. To aid in this process, we have engineered a fluorescent reporter in human embryonic stem cells, which, when the stem cells are turned into corticospinal motor neurons and related subcerebral projection neurons, will light up – literally. We will probe the molecular control of this process and determine if corticospinal motor neurons made in a culture dish, when introduced back into an organism, can send projections to the spinal cord, as they would normally do during development. Most of our knowledge about the development of corticospinal motor neurons comes from studies with mouse models. As there are likely to be important differences between humans and mice, we will pay special attention to the similarities and differences between mouse and human corticospinal motor neurons. Knowledge gained from this study will pave the way to make better disease-models-in-a-dish for neurological conditions such as ALS and to develop therapies for ALS, spinal cord injury, traumatic brain injury, stroke and other neurological conditions when corticospinal motor neurons are damaged.
Statement of Benefit to California: 
Neurological conditions affect millions of Californians each year. Spinal cord injury is one particularly debilitating neurological condition. 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 million annually for the state of California. Research is the only solution as currently there is no cure for spinal cord injury. A major functional deficit for patients of spinal cord injury is the loss of motor control. Corticospinal motor neurons mediate skilled, voluntary movement in humans and damage to these neurons leads to severe disability. Our proposed study focuses on the understanding of how corticospinal motor neurons and, more broadly, subcerebral projection neurons can be made from human embryonic stem cells under culture conditions, and how they can be introduced back to central nervous system. Understanding this process will allow scientists to design ways to use these cells for transplantation therapies not only for spinal cord injury, but also for other neurological conditions such as amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease). Effective treatments promoting functional repair will significantly increase personal independence for people with spinal cord injury and 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 injury, ALS and other neurological conditions.
Progress Report: 
  • A major goal of stem cell research is to generate various functional human cell types to promote repair or replacement in injury or disease. Our lab studies the repair of central nervous system after injury such as a spinal cord injury. We have been utilizing a fluorescent reporter line we developed with CIRM funding to enrich and characterize human corticospinal motor neurons, a neuronal population that is damaged or lost in spinal cord injury and amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease). These neurons control skilled voluntary movement in humans, the loss or damage of which leads to paralysis and disability. We have made significant progress in this funding period. We validated that our fluorescent reporter works as intended. We found that reporter gene expression represents cells of different developmental stages at different times of differentiation. We have done the first batches of transplantation studies to show that it is possible to use the reporter gene to track the cells and cellular processes in the host central nervous system. In addition, we have developed a separate reporter gene to universally mark all embryonic stem-derived cells, a tool that may be useful to other stem cell researchers. We are now ready to move to the next phase of the project: to characterize corticospinal motor neurons in more detail in vitro and in vivo. Knowledge gained from this study will pave the way to make better disease-models-in-a-dish for neurological conditions such as ALS and to develop therapies for ALS, spinal cord injury, traumatic brain injury, stroke and other neurological conditions when corticospinal motor neurons are damaged of lost.
  • A major goal of stem cell research is to generate various functional human cell types to promote repair or replacement in injury or disease. Our lab studies the repair of central nervous system after injury such as a spinal cord injury. We have been utilizing a fluorescent reporter line we developed with CIRM funding to derive and characterize human corticospinal motor neurons, a neuronal population that is damaged or lost in spinal cord injury and amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease). These neurons are of paramount importance to skilled voluntary movement in humans, the loss or damage of which leads to paralysis and disability. The goal for making a reporter line is that whenever the cells light up (literally), we will know what they have become the type of cells that we would wish to get. Following last year’s initial progress, we have made significant progress in this funding period. We found that our fluorescent reporter is useful in following the desired cell types throughout cell growth in culture dishes or after we introduce these cells into animal models by transplantation. We have performed experiments to validate the identity and usefulness of these cells. In culture, these cells exhibit the desired signature gene expression pattern, electrophysiological properties and morphologies as well. We will continue to improve our culture condition to maximize efficiency and purity. Meanwhile, we have transplanted these cells into the mouse brain to study them in the complex central nervous system because many of the properties cannot be studied in cell culture such as the connection of nerve cells to other brain area or spinal cord. We were excited to find that these cells, once transplanted, can survive, integrate into the mouse central nervous system, and send out long neuronal processes characteristic of endogenous nerve cells. Some of the projections appear to take the path of the projections of the corticospinal motor neurons, indicating that our approach will likely succeed. Thanks to CIRM’s support, we will continue to investigate the various parameters to improve our transplantation studies. Knowledge gained from this study will pave the way to make better disease-models-in-a-dish for neurological conditions such as ALS and to develop therapies for ALS, spinal cord injury, traumatic brain injury, stroke and other neurological conditions when corticospinal motor neurons are damaged of lost.

A Phase I/IIa Dose Escalation Safety Study of AST-OPC1 in Patients with Cervical Sensorimotor Complete Spinal Cord Injury

Funding Type: 
Strategic Partnership III Track A
Grant Number: 
SP3A-07552
ICOC Funds Committed: 
$14 323 318
Disease Focus: 
Spinal Cord Injury
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 
The proposed project is designed to assess the safety and preliminary activity of escalating doses of human embryonic stem cell derived oligodendrocyte progenitor cells (OPCs) for the treatment of spinal cord injury. OPCs have two important functions: they produce factors which stimulate the survival and growth of nerve cells after injury, and they mature in the spinal cord to produce myelin, the insulation which enables electrical signals to be conducted within the spinal cord. Clinical testing of this product initiated in 2010 after extensive safety and efficacy testing in more than 20 nonclinical studies. Initial clinical safety testing was conducted in five subjects with neurologically complete thoracic injuries. No safety concerns have been observed after following these five subjects for more than two years. The current project proposes to extend testing to subjects with neurologically complete cervical injuries, the intended population for further clinical development, and the population considered most likely to benefit from the therapy. Initial safety testing will be performed in three subjects at a low dose level, with subsequent groups of five subjects at higher doses bracketing the range believed most likely to result in functional improvements. Subjects will be monitored both for evidence of safety issues and for signs of neurological improvement using a variety of neurological, imaging and laboratory assessments. By completion of the project, we expect to have accumulated sufficient safety and dosing data to support initiation of an expanded efficacy study of a single selected dose in the intended clinical target population.
Statement of Benefit to California: 
The proposed project has the potential to benefit the state of California by improving medical outcomes for California residents with spinal cord injuries (SCIs), building on California’s leadership position in the field of stem cell research, and creating high quality biotechnology jobs for Californians. Over 12,000 Americans suffer an SCI each year, and approximately 1.3 million people in the United States are estimated to be living with a spinal cord injury. Although specific estimates for the state of California are not available, the majority of SCI result from motor vehicle accidents, falls, acts of violence, and recreational sporting activities, all of which are common in California. Thus, the annual incidence of SCI in California is likely equal to or higher than the 1,400 cases predicted by a purely population-based distribution of the nationwide incidence. The medical, societal and economic burden of SCI is extraordinarily high. Traumatic SCI most commonly impacts individuals in their 20s and 30s, resulting in a high-level of permanent disability in young and previously healthy individuals. At one year post injury, only 11.8% of SCI patients are employed, and fewer than 35% are employed even at more than twenty years post-injury (NSCISC Spinal Cord Injury Facts and Figures 2013). Life expectancies of SCI patients are significantly below those of similar aged patients with no SCI. Additionally, many patients require help with activities of daily living such as feeding and bathing. As a result, the lifetime cost of care for SCI patients are enormous; a recent paper (Cao et al 2009) estimated lifetime costs of care for a patient obtaining a cervical SCI (the population to be enrolled in this study) at age 25 at $4.2 million. Even partial correction of any of the debilitating consequences of SCI could enhance activities of daily living, increase employment, and decrease reliance on attendant and medical care, resulting in substantial improvements in both quality of life and cost of care for SCI patients. California has a history of leadership both in biotechnology and in stem cell research. The product described in this application was invented in California, and has already undergone safety testing in five patients in a clinical study initiated by a California corporation. The applicant, who has licensed this product from its original developer and recruited many of the employees responsible for its previous development, currently employs 17 full-time employees at its California headquarters, with plans to significantly increase in size over the coming years. The successful performance of the proposed project would enable significant additional jobs creation in preparation for pivotal trials and product registration.

Elucidating pathways from hereditary Alzheimer mutations to pathological tau phenotypes

Funding Type: 
Basic Biology V
Grant Number: 
RB5-07011
ICOC Funds Committed: 
$1 161 000
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Closed
Public Abstract: 
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.
Statement of Benefit to California: 
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.

Molecular basis of plasma membrane characteristics reflecting stem cell fate potential

Funding Type: 
Basic Biology V
Grant Number: 
RB5-07254
ICOC Funds Committed: 
$1 003 590
Disease Focus: 
Neurological Disorders
Stem Cell Use: 
Adult Stem Cell
oldStatus: 
Closed
Public Abstract: 
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.
Statement of Benefit to California: 
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.

Paracrine and synaptic mechanisms underlying neural stem cell-mediated stroke recovery

Funding Type: 
Basic Biology V
Grant Number: 
RB5-07363
ICOC Funds Committed: 
$1 178 370
Disease Focus: 
Stroke
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 
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, SD56 cells, to the clinic for stroke therapy in a CIRM-funded Disease Team program. 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.
Statement of Benefit to California: 
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.

Misregulated Mitophagy in Parkinsonian Neurodegeneration

Funding Type: 
Basic Biology V
Grant Number: 
RB5-06935
ICOC Funds Committed: 
$1 174 943
Disease Focus: 
Parkinson's Disease
Neurological Disorders
Stem Cell Use: 
iPS Cell
oldStatus: 
Closed
Public Abstract: 
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.
Statement of Benefit to California: 
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.

Molecular Imaging for Stem Cell Science and Clinical Application

Funding Type: 
Research Leadership 12
Grant Number: 
LA1_C12-06919
ICOC Funds Committed: 
$6 443 455
Disease Focus: 
Amyotrophic Lateral Sclerosis
Neurological Disorders
Spinal Cord Injury
oldStatus: 
Active
Public Abstract: 
Stem cells offer tremendous potential to treat previously intractable diseases. the clinical translation of these therapies, however, presents unique challenges. One challenge is the absence of robust methods to monitor cell location and fate after delivery to the body. The delivery and biological distribution of stem cells over time can be much less predictable compared to conventional therapeutics, such as small-molecule therapeutic drugs. This basic fact can cause road blocks in the clinical translation, or in the regulatory path, which may cause delays in getting promising treatments into patients. My research aims to meet these challenges by developing new non-invasive cell tracking platforms for emerging stem cell therapies. Recent progress in magnetic resonance imaging (MRI) has demonstrated the feasibility of non-invasive monitoring of transplanted cells in patients. This project will build on these developments by creating next-generation cell tracking technologies with improved detectability and functionality. Additionally, I will provide leadership in the integration of non-invasive cell tracking into stem cell clinical trials. Specifically, this project will follow three parallel tracks. (1) The first track leverages molecular genetics to develop new nucleic acid-based MRI reporters. These reporters provide instructions to program a cell’s innate machinery so that they produce special proteins with magnetic properties that impart MRI contrast to cells, and allow the cells to be seen. My team will create neural stem cell lines with MRI reporters integrated into their genome so that those neural stem cell lines, and their daughter cells, can be tracked days and months after transfer into a patient. (2) The second track will develop methods to detect stem cell viability in vivo using perfluorocarbon-based biosensors that can measure a stem cell's intracellular oxygen level. This technology can potentially be used to measure stem cell engraftment success, to see if the new cells are joining up with the other cells where they are placed. (3) The third project involves investigating the role that the host’s inflammatory response plays in stem cell engraftment. These studies will employ novel perfluorocarbon imaging probes that enable MRI visualization and quantification of places in the body where inflammation is occurring. Overall, MRI cell tracking methods will be applied to new stem cell therapies for amyotrophic lateral sclerosis, spinal cord injury, and other disease states, in collaboration with CIRM-funded investigators.
Statement of Benefit to California: 
California leads the nation in supporting stem cell research with the aim of finding cures for major diseases afflicting large segments of the state’s population. Significant resources are invested in the design of novel cellular therapeutic strategies and associated clinical trials. To accelerate the clinical translation of these potentially live saving therapies, many physicians need method to image the behavior and movement of cells non-invasively following transplant into patients. My research aims to meet these challenges by developing new cell tracking imaging platforms for emerging stem cell therapies. Recent progress in magnetic resonance imaging (MRI) has demonstrated the feasibility of non-invasive monitoring of transplanted cells in patients. This project will build on these developments by leading the integration of MRI cell tracking into stem cell clinical trials and by developing next-generation technologies with improved sensitivity and functionality. Initially, MRI cell tracking methods will be applied to new stem cell therapies for amyotrophic lateral sclerosis and spinal cord injury. In vivo MRI cell tracking can accelerate the process of deciding whether to continue at the preclinical and early clinical trial stages, and can facilitate smaller, less costly trials by enrolling smaller patient numbers. Imaging can potentially yield data about stem cell engraftment success. Moreover, MRI cell tracking can help improve safety profiling and can potentially lower regulatory barriers by verifying survival and location of transplanted cells. Overall, in vivo MRI cell tracking can help maximize the impact of the State’s investment in stem cell therapies by speeding-up clinical translation into patients. These endeavors are intrinsically collaborative and multidisciplinary. My project will create a new Stem Cell Imaging Center (SCIC) in California with a comprehensive set of ways to elucidate anatomical, functional, and molecular behavior of stem cells in model systems. The SCIC will provide scientific leadership to stem cell researchers and clinicians in the region, including a large number of CIRM-funded investigators who wish to bring state-of-the-art imaging into their clinical development programs. Importantly, the SCIC will focus intellectual talent on biological imaging for the state and the country. This project will help make MRI cell tracking more widespread clinically and position California to take a leadership role in driving this technology. An extensive infrastructure of MRI scanners already exist in California, and these advanced MRI methods would use this medical infrastructure better to advance stem cell therapies. Moreover, this project will lead to innovative new MRI tools and pharmaceutical imaging agents, thus providing economic benefits to California via the formation of new commercial products, industrial enterprises, and jobs.

Stem Cell-Derived Astrocyte Precursor Transplants in Amyotrophic Lateral Sclerosis

Funding Type: 
Early Translational from Disease Team Conversion
Grant Number: 
TRX-01471
ICOC Funds Committed: 
$4 139 754
Disease Focus: 
Amyotrophic Lateral Sclerosis
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 
Statement of Benefit to California: 
Progress Report: 
  • Project Description and Rationale:
  • Amyotrophic Lateral Sclerosis (ALS) is the most common adult motor neuron disease, affecting 30,000 people in the US and the typical age of onset is in the mid-50s or slightly younger. ALS is a degenerative neural disease in which the damage and death of neurons results in progressive loss of the body’s functions until death, which is usually in 3-5 years of diagnosis. Current ALS treatments are primarily supportive, and providing excellent clinical care is essential for patients with ALS; however, there is an urgent need for treatments that significantly change the disease course. The only Food and Drug Administration approved, disease-specific medication for treatment of ALS is Rilutek (riluzole); which demonstrated only a modest effect on survival (up to 3 months) in clinical trials.
  • The ALS Disease Team/Early Translational project is focused on developing an ALS therapy based on human embryonic stem cell (ESC) derived neural stem cells (NSC) and/or astrocyte precursor cells transplanted into the ventral horn of the spinal cord. Several lines of evidence strongly support the approach of transplanting cells that exhibit the capacity to migrate, proliferate and mature into normal healthy astrocytes which can provide a neuroprotective effect for motor neurons and reduce or prevent neural damage and disease progression in ALS. Strong evidence has been generated from extensive studies in culture dishes and in animal models to support the concept that providing normal astrocytes in the proximity of α-motor neurons can protect them from neural damage.
  • Project Plan and Progress:
  • Multiple ESC lines were acquired in 2 rounds based on early and later availability. The first round of ESCs included ESCs from City of Hope (GMP H9) and the University of California, San Francisco (UCSF4). The second round included ESCs from the University of California, San Francisco [UCSFB6 (aka UCSF4.2) and UCSFB7 (aka UCSF4.3)] and from BioTime (ESI-017). These ESC lines were tested for their ability to survive and expand under conditions required for producing a cellular therapy (FDA GMP-like and GTP compliant conditions). From these ESC lines, NSCs were generated, expanded and characterized to determine their ability to produce stable and consistent populations of NSCs under conditions required for producing a cellular therapy.
  • For the first round of cell lines, both UCSF4 and H9 were successfully induced to produce NSCs, which were mechanically enriched, expanded and implanted into immunodeficient rats and a rat model of ALS (SOD1G93A). For this small-scale in vivo screen, implanted UCSF4 and H9 NSCs survived, migrated and differentiated into neurons and astrocytic cells in 3-5 weeks, without producing tumors or other unwanted structures. NSCs from both UCSF4 and H9 performed similarly in culture and in vivo, thus the decision to use UCSF4 in the larger-scale in vivo studies for safety (implant into immunodeficient rats) and efficacy/proof of concept (SOD1G93A ALS model rats) was weighted by the difficulties obtaining H9 for future studies for a therapeutic product. These larger-scale studies began August 2013 (earlier than projected), with expected completion in February 2014.
  • For the second round of ESC lines (UCSFB6, UCSFB7 and BioTime ESI-017), UCSFB6 and UCSFB7 ESCs expanded well, while ESI-017 expansion was less robust. Because UCSFB6 and UCSFB7 ESCs are from the same blastomere, we decided to continue to NSC production with only UCSFB7, keeping UCSFB6 in reserve as a back-up. UCSFB7 ESCs were successfully induced to produce NSCs, which were mechanically enriched, expanded and implanted into immunodeficient rats and a rat model of ALS (SOD1G93A). The results from these studies are pending (some animals are still in-life), but early histology suggests the cell survival is similar to UCSF4 and H9. A second round of large-scale in vivo studies is planned to start January 2014 to evaluate this NSC line. By September 2014, the “best” NSC line will be selected as a therapeutic candidate for definitive pre-clinical studies and entry into clinical trials.
  • ESC production under GMP-like condition has been completed at the UC Davis GMP facility. UC Davis generated the first batch of NSCs, which were not sufficiently homogeneous for successful expansion beyond approximately passage 10. This prompted UCSD to investigate multiple enrichment strategies, which were tested on multiple cell lines to ensure method reproducibility. A mechanical enrichment method reproducibly resulted in more homogeneous NSC cultures, capable of expansion for 20 – 30 passages, or more. The NSC generation and enrichment methods are currently being transferred to UC Davis and the UCSD scientist who developed the methods will work side-by-side with the UC Davis GMP production team to ensure successful method transfer to the GMP facility.
  • UCSF4 NSCs are also in use in a CIRM supported early translation study for spinal cord injury.

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