Neurological Disorders

Coding Dimension ID: 
303
Coding Dimension path name: 
Neurological Disorders
Funding Type: 
Early Translational III
Grant Number: 
TR3-05617
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$4 327 175
Disease Focus: 
Multiple Sclerosis
Neurological Disorders
Stem Cell Use: 
Adult Stem Cell
Cell Line Generation: 
Adult Stem Cell
oldStatus: 
Active
Public Abstract: 
Multiple sclerosis (MS) is an autoimmune disease in which the myelin sheath that insulates neurons is destroyed, resulting in loss of proper neuronal function. Existing treatments for MS are based on strategies that suppress the immune response. While these drugs do provide benefit by reducing relapses and delaying progression (but have significant side effects), the disease invariably progresses. We are pursuing an alternative therapy aimed at regeneration of the myelin sheath through drugs that act on an endogenous stem cell population in the central nervous system termed oligodendrocyte precursor cells (OPCs). Remission in MS is largely dependent upon OPCs migrating to sites of injury and subsequently differentiating into oligodendrocytes – the cells that synthesize myelin and are capable of neuronal repair. Previous studies indicate that in progressive MS, OPCs are abundantly present at sites of damage but fail to differentiate to oligodendrocytes. As such, drug-like molecules capable of inducing OPC differentiation should have significant potential, used alone or in combination with existing immunomodulatory agents, for the treatment of MS. The objective of this project is to identify a development candidate (DC) for the treatment of multiple sclerosis (MS) that functions by directly stimulating the differentiation of the adult stem cells required for remyelination.
Statement of Benefit to California: 
Multiple Sclerosis (MS) is a painful, neurodegenerative disease that leads to an impairment of physical and cognitive abilities. Patients with MS are often forced to stop working because their condition becomes so limiting. MS can interfere with a patient's ability to even perform simple routine daily activities, resulting in a decreased quality of life. Existing treatments for MS delay disease progression and minimize symptoms, however, the disease invariably progresses to a state of chronic demyelination. The goal of this project is to identify novel promyelinating drugs, based on differentiation of an endogenous stem cell population. Such drugs would be used in combination with existing immunosuppressive drugs to prevent disease progression and restore proper neuronal activity. More effective MS treatment strategies represent a major unmet medical need that could impact the roughly 50,000 Californians suffering from this disease. Clearly the development of a promyelinating therapeutic would have a significant impact on the well-being of Californians and reduce the negative economic impact on the state resulting from this degenerative disease.
Progress Report: 
  • Multiple sclerosis (MS) is an autoimmune disease characterized by the destruction of the myelin sheath that insulates neurons, resulting in loss of proper neuronal function. Existing treatments for MS are based exclusively on strategies that suppress the immune response. We are pursuing an alternative stem cell-based therapeutic approach aimed at enhancing regeneration of the myelin sheath. Specifically, we are focused on the identification of drug-like molecules capable of inducing oligodendrocyte precursor cell (OPC) differentiation. To date, we have identified a series approved drugs that effectively induce OPC differentiation under tissue culture conditions. Additionally, we have demonstrated that several of these drug candidates reduce MS-like symptoms in relevant rodent models of the disease. We are currently conducting detailed pharmacology experiments to determine which of the identified molecules will serve as the best candidate for future clinical development.
  • The aim of this project is to identify and characterize molecules that induce the repair of lesions in multiple sclerosis. Molecules that induce the selective differentiation of oligodendrocyte precursor cells to oligodendrocytes and thereby lead to remyelination of axons are being characterized with respect to their in vitro activity and in vivo efficacy in relevant animal models, alone and in combination with immunosuppressive drugs. This work may lead to a new regenerative therapy for multiple sclerosis that is complementary to the current immune-focused therapies.
Funding Type: 
Early Translational III
Grant Number: 
TR3-05476
Investigator: 
ICOC Funds Committed: 
$5 509 978
Disease Focus: 
Neurological Disorders
Pediatrics
Stem Cell Use: 
Adult Stem Cell
Cell Line Generation: 
Adult Stem Cell
oldStatus: 
Active
Public Abstract: 
Children with inherited degenerative diseases of the brain will be among the first to benefit from novel approaches based on stem cell therapy (SCT). This assertion is based on a number of medical and experimental observations and precedents including: 1) These diseases currently lack effective therapies and can cause profound mental retardation or lead to death; 2) SCT has already been shown to work in the milder forms of similar diseases that do not affect the brain; 3) Experimental work and early clinical studies have clearly shown that stem cells delivered directly into the brain can be used to treat diseases affecting the brain; and 4) The clinical safety of stem cells delivered directly into the brain has already been established during recent Phase 1 clinical trials. Our approach is designed to lead to a therapeutic development candidate, based on stem cells, by addressing two critical issues: (i) that early intervention is not only required but is indeed possible in this patient population and that, (ii) induction of immune tolerance is also required. We not only address these two important issues but also set the stage for efficient translation of our approach into clinical practice, by adapting transplant techniques that are standard in clinical practice or in clinical trials and using laboratory cell biology methods that are easily transferrable to the scale and processes of clinical cell manufacturing.
Statement of Benefit to California: 
We are focusing on a class of childhood brain diseases that causes a child's brain to degenerate and results in severe mental retardation or death, in addition to damage to many other organ systems. These diseases are not yet represented in CIRM’s portfolio. Recently blood stem cell transplantation has been applied to these diseases, showing that some of the organ systems can be rescued by stem cell therapy. Unfortunately, the brain component of the disease is not impacted by blood stem cell therapy. Our team proposes to take these important lessons to develop a therapy that treats all organ dysfunction, including brain. Because of the established stem cell success in the clinical treatment of non-brain organs and the experimental treatment of the brain, we propose a novel, combined stem cell therapy. Based on our own work and recent clinical experience, this dual stem cell therapy has a high probability of success for slowing or reversing disease, and importantly, will not require children to be treated with toxic immunosuppressive drugs. This therapy will thus benefit California by: 1) reducing disease burden in individuals and the State's burden for caring for these children; 2) providing a successful model of stem cell therapy of the brain that will both bolster public confidence in CIRM's mission to move complex stem cell therapies into the clinic; and 3) laying the groundwork for using this type of therapy with other brain diseases of children.
Progress Report: 
  • The purpose of the ET3RA is to establish an experimental model of stem cell transplantation that accomplishes two equally important goals: 1) to devise a strategy of protection of the child's brain from the ravages of certain genetic diseases and 2) to devise a simultaneous strategy of transplantation that avoids immune system rejection. In our first year of work, we have shown that we can reliably produce the stem cells that we want to transplant into the brains of experimental animals (mice). We have also bred sufficient numbers of mice for the transplant experiments and have started the immune system-based strategy of transplantation. This puts us in the proper position to begin the brain stem cell transplantation in year 2. Thus, we are on course to accomplishing our goals for this ET3RA and for eventual development of this strategy for the initiation of clinical trials.
  • The purpose of the ET3RA is to establish an experimental model of stem cell transplantation that accomplishes two equally important goals: 1) to devise a strategy of protection of the child's brain from the ravages of certain genetic diseases and 2) to devise a simultaneous strategy of transplantation that avoids immune system rejection. In our first year of work, we have shown that we can reliably produce the stem cells that we want to transplant into the brains of experimental animals (mice). We have also bred sufficient numbers of mice for the transplant experiments and have started the immune system-based strategy of transplantation. During the second year, we successfully finished our first round of transplantation experiments, we fully characterized the stem cells for brain transplantation, we showed that the cells have the desired biological effects in the culture dish, and we completed installation of our Cell Production Facility. Thus, we are still on course to accomplishing our goals for this ET3RA and for eventual development of this strategy for the initiation of clinical trials.
Funding Type: 
Early Translational III
Grant Number: 
TR3-05577
Investigator: 
ICOC Funds Committed: 
$1 857 600
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
We propose to discover new drug candidates for 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 candidates 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 drugs 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 drugs 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 to drug discovery for AD.
Progress Report: 
  • We have made steady and significant progress in developing a way to use human reprogrammed stem cells to develop drugs for Alzheimer's disease. In the more recent project term we have further refined our key assay, and generated sufficient cells to enable screening of 50,000 different chemical candidates that might reveal potential drugs for this terrible disease. With a little bit of additional refinement, we will be able to begin our search in earnest in collaboration with the Sanford-Burnham Prebys Screening Center.
  • During the past year we completed screening of our Alzheimers “disease in a dish” cultured stem cell lines for response of a critical measure of Alzheimers disease in a dish to FDA approved drugs and other potentially promising drug like compounds. We found several reproducible and interesting categories of potential drugs some of which are already in common use in human patients and therefore might be readily available to the Alzheimer's disease population. We are conducting more careful analyses of these drugs for their mechanism and behavior in human neurons with different types of Alzheimer like behavior and we are beginning to test whether all human variants behave the same way as preparation for potential clinical trials. We are also initiating analysis of new chemical entities for possible modification to improve potency.
Funding Type: 
Early Translational III
Grant Number: 
TR3-05606
Investigator: 
ICOC Funds Committed: 
$1 623 251
Disease Focus: 
Spinal Cord Injury
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 
Transplantation of neuronal precursors into the central nervous system offers great promise for the treatment of neurological disorders including spinal cord injury (SCI). Among the most significant consequences of SCI are bladder spasticity and neuropathic pain, both of which likely result from a reduction in those spinal inhibitory mechanisms that are essential for normal bladder and sensory functions. Our preliminary data show that embryonic inhibitory neuron precursor cells integrate in the adult nervous system and increase inhibitory network activity. Therefore inhibitory nerve cell transplants could be a powerful way to establish new inhibitory circuits in the injured spinal cord that will reduce bladder spasticity and attenuate central neuropathic pain. We already have proof-of-principle data that murine inhibitory nerve cells integrate in the adult spinal cord and improve symptoms in an animal model of chronic spinal cord injury. We have also recently developed methods to create human inhibitory interneurons from embryonic stem cells. This proposal will capitalize on these recent developments and determine whether our human embryonic stem cell-derived inhibitory cells can be successfully transplanted into the grey matter of the injured spinal cord and reduce neurogenic bladder dysfunction and neuropathic pain, two major causes of suffering in chronic SCI patients. If successful, our studies will lay the groundwork for a potential novel therapy for chronic SCI.
Statement of Benefit to California: 
There are an estimated 260,000 individuals in the United States who currently live with disability associated with chronic spinal cord injury (SCI). Symptoms of chronic SCI include bladder dyssynergia reflected by incontinence coincident with asynchronous contraction of internal and external sphincters, and central neuropathic pain, both of which severely impede activities of daily living, reduce quality of life, and contribute to the very high medical costs of caring for the Californians who suffer from chronic spinal cord injury. The Geron trial for SCI, as well as other cell-based approaches, aim to treat acute SCI. This proposal considers a different potentially complementary cell-transplantation strategy that is directed to more chronic SCI with the goal of improving bladder function and reducing pain. We propose to use cell grafts of inhibitory interneurons that we have derived from human stem cells in order to provide a novel treatment. If successful, we will have defined a therapeutic option that targets the most prevalent population of spinal cord injured patients. As the country's most populous state, California has the largest number of patients with chronic SCI, approximately 12,000. The estimated economic cost to California in lost productivity and medical expenses amounts to $400,000,000 annually. The potential savings in medical care costs, and improvement in quality of life will therfore have a disproportional benefit to the state of California.
Progress Report: 
  • From the past six months of work, we report considerable progress toward our aims of investigating the safety and efficacy of human inhibitory nerve precursor (MGE) cell transplantation for the treatment of spinal cord injury-induced bladder spasticity and neuropathic pain. Our first aim details the injection of human MGE cells into the uninjured rodent spinal cord and investigation of cell fate and potential adverse side effects from their transplantation. During the reporting period, we completed histological analyses for the two-month time point post-injection, and we found that the human MGE cells, derived from human embryonic stem cells (hESCs), appropriately matured into forebrain-type inhibitory interneurons in the rodent spinal cord. Also, we initiated histological examination of animals six months post-injection and detected robust human cell survival, dispersal into the spinal cord grey matter, and neuronal maturation, but no evidence of tumor formation. In addition, we completed behavioral analyses of animals injected with hESC-derived MGE cells at two and six months post-injection. Thus far, we have not observed any adverse side effects when human MGE cells are transplanted into the uninjured animal as determined by measures of body weight, locomotion, bladder function, and pain sensitivity.
  • Since the beginning of this project, we report considerable progress toward our aims of investigating the safety and efficacy of human inhibitory nerve precursor (MGE) cell transplantation for the treatment of spinal cord injury-induced bladder spasticity and neuropathic pain. In year one of this award we completed the major objectives of Aim1, namely to explore the survival, integration, and cell fate of stem cell-derived MGE cell transplants in the uninjured rodent spinal cord. We have now obtained preliminary efficacy results from Aim 2, namely the effects of hESC-MGE cells injected in spinal cord injured animals. Behavioral testing has been obtained to assess pain thresholds for all injected animals up to the six month endpoint, and measures of bladder spasticity have been obtained at six months post cell injection. We are evaluating whether the unblinded data demonstrates amelioration of neuropathic pain and bladder spasticity. Our preliminary histological analysis shows robust human cell survival, distribution, and neuronal differentiation, and we have electrophysiological data indicating functional integration of the transplanted cells. We are on track to complete all aims by the end of the award period.
Funding Type: 
Early Translational III
Grant Number: 
TR3-05676
Investigator: 
Name: 
Type: 
PI
ICOC Funds Committed: 
$1 654 830
Disease Focus: 
Amyotrophic Lateral Sclerosis
Neurological Disorders
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
Approximately 5,600 people in the U.S. are diagnosed with ALS each year. The incidence of ALS is two per 100,000 people, and it is estimated that as many as 30,000 Americans may have the disease at any given time. There are no effective therapies of ALS to-date. Recent genetic discoveries have pinpointed mutations that lead to the aberrant function of two proteins that bind to RNA transcripts in neurons. Misregulation of these RNA binding proteins is responsible for the aberrant levels and processing of hundreds of RNA representing genes that are important for neuronal survival and function. In this proposal, we will use neurons generated from patient cells that harbor the mutations in these RNA binding proteins to (1) prioritize a RNA “signature” unique to neurons suffering from the toxic function of these proteins and (2) as an abundant source of raw material to enable high-throughput screens of drug-like compounds that will bypass the mutations in the proteins and “correct” the RNA signature to resemble that of a healthy neuron. If successful, our unconventional approach that uses hundreds of parallel measurements of specific RNA events, will identify drugs that will treat ALS patients.
Statement of Benefit to California: 
Our research aims to develop drug-like compounds that are aimed to treat Amyotrophic Lateral Sclerosis (ALS), which may be applicable to other neurological diseases that heavily impact Californians, such as Frontotemporal Lobar Degeneration, Parkinson’s and Alzheimer’s. The cellular resources and genomic assays that we are developing in this research will have great potential for future research and can be applied to other disease areas. The cells, in particular will be beneficial to California health care patients, pharmaceutical and biotechnology industries in terms of improved human models for drug discovery and toxicology testing. Our improved knowledge base will support our efforts as well as other Californian researchers to study stem cell models of neurological disease and design new diagnostics and treatments, thereby maintaining California's position as a leader in clinical research.
Progress Report: 
  • Our research aims to develop drug-like compounds that are aimed to treat Amyotrophic Lateral Sclerosis (ALS), which may be applicable to other neurological diseases that heavily impact Californians, such as Frontotemporal Lobar Degeneration, Parkinson’s and Alzheimer’s. In the first year, we have succeeded in improving the efficiency of motor neuron differentiation to generate high-quality motor neurons from induced pluripotent stem cells. We have generated RNA signatures from motor neurons differentiated from induced pluripotent stem cells from normal, healthy individuals whereby key proteins implicated in ALS are depleted using RNAi technology. We have also generated motor neurons from induced pluripotent stem cells that contained mutations in these key proteins and are in the process of applying genomic technologies to compare these cells to ones where we have depleted the proteins themselves. In parallel, we have started to optimize conditions for a small molecule screen to identify previously FDA-approved compounds that may alter aberrant and ALS-associated phenotypes in human cell lines.
  • In this reporting period, we have successfully generated lines that we have used to identify small molecules that alter the formation of aggregates in human neural progenitors and non-neuronal cell lines. These molecules will be tested for the reversal of aberrant RNA signatures in motor neurons from patients with ALS-associated mutations.
Funding Type: 
Early Translational III
Grant Number: 
TR3-05603
Investigator: 
Type: 
PI
Type: 
Co-PI
Institution: 
Type: 
Partner-PI
ICOC Funds Committed: 
$4 799 814
Disease Focus: 
Multiple Sclerosis
Neurological Disorders
Collaborative Funder: 
Australia
Stem Cell Use: 
Embryonic Stem Cell
iPS Cell
oldStatus: 
Active
Public Abstract: 
Multiple Sclerosis (MS) is a disease of the central nervous system (CNS) caused by inflammation and loss of cells that produce myelin, which normally insulates and protects nerve cells. MS is a leading cause of neurological disability among young adults in North America. Current treatments for MS include drugs such as interferons and corticosteroids that modulate the ability of immune system cells to invade the CNS. These therapies often have unsatisfactory outcomes, with continued progression of neurologic disability over time. This is most likely due to irreversible tissue injury resulting from permanent loss of myelin and nerve destruction. The limited ability of the body to repair damaged nerve tissue highlights a critically important and unmet need for MS patients. The long-term goal of our research is to develop a stem cell-based therapy that will not only halt ongoing loss of myelin but also lead to remyelination and repair of damaged nerve tissue. Our preliminary data in animal models of human MS are very promising and suggest that this goal is possible. Research efforts will concentrate on refining techniques for production and rigorous quality control of clinically-compatible transplantable cells generated from high-quality human pluripotent stem cell lines, and to verify the therapeutic activity of these cells. We will emphasize safety and development of the most therapeutically beneficial cell type for eventual use in patients with MS.
Statement of Benefit to California: 
One in seven Americans lives in California, and these people make up the single largest health care market in the United States. The diseases and injuries that affect Californians affect the rest of the US and the world. Many of these diseases involve degeneration of healthy cells and tissues, including neuronal tissue in diseases such as Multiple Sclerosis (MS). The best estimates indicate that there are 400,000 people diagnosed with MS in the USA and 2.2 million worldwide. In California, there are approximately 160,000 people with MS – roughly half of MS patients in the US live in California. MS is a life-long, chronic disease diagnosed primarily in young adults who have a virtually normal life expectancy but suffer from progressive loss of motor and cognitive function. Consequently, the economic, social and medical costs associated with the disease are significant. Estimates place the annual cost of MS in the United States in the billions of dollars. The development of a stem cell therapy for treatment of MS patients will not only alleviate ongoing suffering but also allow people afflicted with this disease to return to work and contribute to the economic stabilization of California. Moreover, a stem cell-based therapy that will provide sustained recovery will reduce recurrence and the ever-growing cost burden to the California medical community.
Progress Report: 
  • The team has been highly productive during the first year of work on this award. A major goal of the project is to evaluate the efficacy of neural progenitor cell transplantation to promote remyelination following virus induced central nervous system damage. With intracranial infection by the virus mouse hepatitis virus (MHV), mice develop paralysis due to immune mediated destruction of cells that generate myelin. Using protocols developed in the Loring laboratory, neural precursor cells (NPC) were derived from the human embryonic stem cell line H9. Mice developing paralysis due to intracranial infection with MHV were subject to intraspinal transplantation of these NPC, resulting in significant clinical recovery beginning at 2-3 weeks following transplant. This clinical effect of NPC transplantation remained out to six months, suggesting that these NPC are effective for long-term repair following demyelination. Despite this striking recovery, these human ES cell derived NPC were rapidly rejected. Several protocols for the generation of NPC for transplantation have been characterized, with the greatest clinical impact observed for NPC cultures bearing a high level of expression of TGF beta I and TGF beta II. These findings support the hypothesis that transplanted NPC reprogram the immune system within the central nervous system (CNS), leading to the activation of endogenous NPC and other repair mechanisms. Thus, it may not be necessary to induce complete immune suppression in order to promote remyelination and CNS repair following NPC transplantation for demyelinating diseases such as multiple sclerosis.
  • The team has been highly productive during the first two years of work on this award. A major goal of the project is to evaluate the efficacy of neural progenitor cell transplantation to promote remyelination following virus induced central nervous system damage. With intracranial infection by the virus mouse hepatitis virus (MHV), mice develop paralysis due to immune mediated destruction of cells that generate myelin. Using protocols developed in the Loring laboratory, neural precursor cells (NPC) were derived from the human embryonic stem cell line H9. Mice developing paralysis due to intracranial infection with MHV were subject to intraspinal transplantation of these NPC, resulting in significant clinical recovery beginning at 2-3 weeks following transplant. This clinical effect of NPC transplantation remained out to six months, suggesting that these NPC are effective for long-term repair following demyelination. Despite this striking recovery, these human ES cell derived NPC were rapidly rejected. Several protocols for the generation of NPC for transplantation have been characterized, with the greatest clinical impact observed for NPC cultures bearing a high level of expression of TGF beta I and TGF beta II. These findings support the hypothesis that transplanted NPC reprogram the immune system within the central nervous system (CNS), leading to the activation of endogenous NPC and other repair mechanisms. Thus, it may not be necessary to induce complete immune suppression in order to promote remyelination and CNS repair following NPC transplantation for demyelinating diseases such as multiple sclerosis. In addition, the group is currently assessing the impact of NPCs in experimental autoimmune encephalomyelitis (EAE), an autoimmune model of MS. Initial results suggest that NPCs also reduce the severity of disease in this model, and studies are underway to determine the mechanism(s) by which NPCs promote clinical recovery during EAE.
Funding Type: 
Disease Team Therapy Planning I
Grant Number: 
DR2-05431
Investigator: 
ICOC Funds Committed: 
$99 976
Disease Focus: 
Parkinson's Disease
Neurological Disorders
oldStatus: 
Closed
Public Abstract: 
Ongoing degeneration of dopaminergic (DA) neurons in the midbrain is the hallmark of Parkinson’s disease (PD), a movement disorder that manifests with tremor, bradykinesia and rigidity. One million Americans live with PD and 60,000 are diagnosed with this disease each year. Although the cost is $25 billion per year in the United States alone, existing therapies for PD are only palliative and treat the symptoms but do not address the underlying cause. Levodopa, the gold standard pharmacological treatment to restore dopamine, is compromised over time by decreased efficacy and particularly increased side effects over time. Neural transplantation is a promising strategy for improving dopaminergic dysfunction in PD. The rationale behind neural transplantation is that grafting cells that produce DA into the denervated striatum will reestablish regulated neurotransmission and restore function. Indeed, over 20 years of research using fetal mesencephalic tissue as a source of DA neurons has demonstrated the therapeutic potential of cell transplantation therapy in animal model of PD and in human patients. However, there are limitations associated with primary human fetal tissue transplantation, including high tissue variability, lack of scalability, ethical concerns and inability to obtain an epidemiologically meaningful quantity of tissue. Thus, the control of the identity, purity and potency of these cells becomes exceedingly difficult and jeopardizes both the safety of the patient and the efficacy of the therapy. Thus the search of self-renewable sources of cells is a very worthwhile goal with societal importance and commercial application. Human neural stem cells are currently the only potential reliable and continuous source of homogenous and qualified populations of DA neurons for cell therapy for PD. Such cell source is ideal for developing a consistently safe and efficacious cellular product for treating large number of PD patients in California and throughout the world We have developed a human neural stem cell line with midbrain dopaminergic properties and the technology to make 75% of the neuronal population express dopamine. We have also shown that these cells are efficacious in the most authentic animal model of PD. We now propose to conduct the manufacturing of these cells in conjunction with the safety and efficacy testing to bring this much needed cellular product to PD patients and treat this devastating disease.
Statement of Benefit to California: 
In this grant application we propose to develop a unique technology to manufacture neurons that will be used to treat patients suffering from Parkinson’s disease. One million Americans live with PD and 60,000 are diagnosed with this disease each year. Although the cost is $25 billion per year in the United States alone, existing therapies for PD are only palliative and treat the symptoms but do not address the underlying cause. Levodopa, the gold standard pharmacological treatment to restore dopamine, is compromised over time by decreased efficacy and increased side effects. Human stem cells are currently the only potential reliable and continuous source of homogenous and qualified populations of DA neurons for cell therapy for PD. Such cell source is ideal for developing a consistently safe and efficacious cellular product for treating large number of PD patients in California and throughout the world We have developed a human neural stem cell line with midbrain dopaminergic properties and the technology to make 75% of the neuronal population express dopamine. We have also shown that these cells are efficacious in the most authentic animal model of PD. We now propose to conduct the manufacturing of these cells and safety and efficacy testing to bring this cell product to PD patients and treat this devastating disease. The CIRM grant will help us create further intellectual property pertaining to the optimization of the process of manufacturing of the cellular product we developed to treat PD. The grant will also create jobs at Californian institutions and contract companies we will work with to develop this product. Importantly, the intellectual property will be made available for licensing to biotechnology companies here in California to develop this product to treat the over 10 million people afflicted with PD world wide. Revenues from such a product will be beneficial to the California economy.
Progress Report: 
  • The planning award allowed the PI and members of the disease team to identify gaps in studies performed to date and strategically plan manufacturing and preclinical IND enabling studies to lead into a phase I clinical trial
  • The PI, Marcel Daadi, PhD assembled a team comprised of neurosurgeons, neurologists and scientists with expertise in Parkinson’s disease, a contract manufacturing organization (CMO) for cell production, a contract research organization (CRO) for the pharmacology and toxicology studies, and accomplished regulatory and project management consultants to work together on developing a cellular product for treating Parkinson’s disease.
  • Together with the members of the disease team, the PI established a detailed strategy to meet the overall goal of the project, to develop a human neural stem cell (NSC) line for transplantation into patients. The team put together a plan to manufacture the cells that included seven stages:
  • STAGE 1: Product manufacturing and process development in the PI laboratory, with CMO’s participation, in preparation for technology transfer including material sourcing, gap analysis of the current manufacturing and analytical process, development of product characterization profile, refinement of manufacturing and analytical procedures and development of requisite documentation.
  • STAGE 2: Technology transfer to CMO, comprised of training and establishing the necessary resources, perform the manufacturing process in house, demonstrate tech transfer and perform runs to manufacture GMP-like cell product suitable for non-GLP animal studies at the CRO facility.
  • STAGE 3: Manufacturing of GLP materials for use in the pre-clinical studies.
  • STAGE 4: Early pre-clinical non-GLP studies using materials that meet product release criteria. The preclinical studies will address critical issues such as delivery devise and approach, immuno-suppression regiment, dose-range finding study, imaging MRI/PET, micro-dialysis, immune response, behavioral outcome, dyskinesias, immunohistopathology and biochemical analysis.
  • STAGE 5: Formal GLP pre-clinical studies using the GMP materials manufactured at CMO with primary efficacy endpoint that is a significant change in the PD score without appearance of dyskinesias.
  • STAGE 6: Regulatory support activities, including pre-pre IND and pre-IND meetings, and compilation and filing of the IND.
  • STAGE 7: Full Process Qualification at the CMO, and manufacture of the GMP cell bank.
  • Among preclinical development studies proposed are a definitive single-dose toxicity and toxicokinetic study in rats with functional observation battery, a one year recovery period (GLP), tumorigenicity in NOD-SCID mice and study to determine dose-range for efficacy and safety in non-human primates.
Funding Type: 
Disease Team Therapy Planning I
Grant Number: 
DR2-05410
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$107 989
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
oldStatus: 
Closed
Public Abstract: 
Alzheimer’s disease (AD) is now a nation-wide epidemic and California is at the epicenter of the epidemic. One-tenth of all people in the United States diagnosed with AD live in California. In the US, 5.4 million people have AD and another American develops AD every 69 seconds. No therapeutic strategies exist to prevent or treat AD. And the situation is worse than expected. Results of a recent two year clinical study show that the currently available medications for managing AD symptoms are ineffective in patients with mild cognitive impairment or mild AD. We seek to develop a small molecule therapeutic, allopregnanolone (APα) to prevent and treat AD. APα promotes the ability of brain to regenerate itself by increasing the number and survival of newly generated neurons. The APα-induced increase in newly generated neurons was associated with a reversal of cognitive deficits and restored learning and memory function to normal in a preclinical mouse model of AD. Further, APα reduced the amount of AD pathology in the brain. Importantly, when given peripherally either by injection under the skin or applied topically to the skin, APα was able to enter the brain to increase the generation of new neurons. The unique mechanism of APα action reduces the risk that APα would cause proliferation of other cells in the body. Because APα was efficacious in both pre-pathology and post-pathology stages of AD progression, APα has the potential to be effective for both the prevention of and early stage treatment of Alzheimer’s disease. Further, APα induced neurogenesis and restoration of cognitive function in normal aged mice suggesting that APα could be efficacious to sustain cognitive function and prevent development of AD in a normal aged population. In other clinical studies, APα has been proven safe in animals and humans and in both men and women. Together, these findings provide a strong foundation on which to plan a clinical trial of APα in persons with prodromal and diagnosed Alzheimer’s disease. To plan for a Phase I-IIa clinical trial to determine safety, dosing and clinical efficacy, we have assembled an interdisciplinary team of clinicians, scientists, therapeutic development, regulatory, data management and statistical analysis experts. The objectives of this proposal are to: a) develop allopregnanolone as a therapeutic for Alzheimer’s disease; to plan an early clinical development program for its use as a neurogenesis agent; b) file a complete and well-supported IND with the Food and Drug Administration (FDA); c) complete phase I/IIa clinical studies to evaluate safety, biological activity, and early efficacy in humans; and (d) complete a phase II clinical trial that will evaluate efficacy and lead to larger multisite clinical studies of efficacy.
Statement of Benefit to California: 
California is at the epicenter of the epidemic of Alzheimer’s disease (AD). Nationwide there are 5.4 million persons living with AD. Ten percent or over half a million Californians have AD. Among California’s baby boomers aged 55 and over, one in eight will develop AD. It is estimated that one in six Californians will develop a form of dementia. By 2030 the number of Californians living with AD will double to over 1.1 million. While all races and ethnic groups and regions of the state will be affected, not all regions within California will be equally affected. Los Angeles County has the greatest population in the state and thus will be the true epicenter of the Alzheimer’s epidemic in California. Alzheimer’s is a disease that affects an entire family, community and health care system. Nation-wide there are nearly 15 million Alzheimer and dementia care givers providing 17 billion hours of unpaid care per year. Total costs for caring for people with AD, totals $183 billion per year. California shouldered $18.3 billion of those costs and most of those costs were born by persons and health care services in Los Angeles County. Because of the psychological and physical toll of caring for people with Alzheimer’s, caregivers had $7.9 billion in additional health care costs. Proportionally that translates into $790 million of health care costs for Californians. In total, California spent over $19 billion per year for costs associated with Alzheimer’s disease. Multiple analyses indicate that a delay of just 5 years can reduce the number of persons diagnosed with Alzheimer’s by 50% and dramatically reduce the associated costs. We seek to develop a small molecule therapeutic, allopregnanolone (APα) to prevent and treat AD. APα promotes the innate regenerative capacity of the brain to increase the pool of neural progenitor cells. The APα-induced increase in neurogenesis was associated with a reversal of cognitive deficits and restored learning and memory function to normal in a preclinical mouse model of AD. Further, APα reduced the development of AD pathology. APα crosses the blood brain barrier and acts through a mechanism unique to neural progenitor cells and thus is unlikely to exert proliferative effects in other organs. Because APα was efficacious in both pre-pathology and post-pathology stages of AD progression, APα has the potential to be effective for both the prevention of and early stage treatment .
Progress Report: 
  • As a result of the planning grant award, the Allopregnanolone (APα) team accomplished the following that enabled submission of the CIRM Disease Team Therapy Development Research Awards Proposal:
  • 1) Created a team of experts in regeneration, neurology and Alzheimer's disease drug development to generate strategy and overall development plan. Through the team’s efforts we developed preclinical and clinical studies, determined correct dosing parameters for clinical studies, identified an optimal route of administration, developed chemistry, manufacturing and controls, and submitted our Pre-IND documents to the FDA.
  • 2) Filed a Pre-IND document with the FDA and held a Pre-IND meeting with the FDA and obtained feedback from the FDA on our program. FDA provided guidance on requirements for the preclinical plan along with input on the design of our two Phase 2 clinical studies. We also obtained agreement that we may cross-reference the existing IND of our academic partner, Michael Rogawski at UC Davis and utilize product manufactured at UC Davis.
  • 3) We developed an integrated CMC plan to manufacture allopregnanolone (clinical API) and established compliant processes to ensure material requirements are met for the preclinical and clinical studies. Manufacture of clinical API will be conducted at the UC Davis CIRM GMP facility.
  • 4) FDA required preclinical IND-enabling research strategy was developed. Teams at USC and a California-based CRO, were identified to conduct three studies: 1) Bridging Study: subcutaneous to IV dosing and administration to bridge from previous subcutaneous preclinical analyses to clinical studies using IV APα administration to determine a) optimal IV dose to promote neurogenesis and b) optimal infusion rate to achieve required peak of APα and area under the curve. 2) Cerebral Microhemorrhage: The FDA advised a safety test for the occurrence of cerebral microhemorrhages localized to the cerebral vasculature in areas of cerebral amyloid angiopathy with various anti-Aβ immunotherapies. 3) Chronic GLP Toxicity Analyses: Based on FDA guidance, safety studies will be required for chronic exposure of Alzheimer’s patients to APα. To initiate the chronic exposure Phase 2a Proof of Concept trial, chronic preclinical toxicology is required. We have designed 6-month and 9-month IV dose GLP toxicity studies in rat and dog, respectively. The studies include systemic toxicology and toxicokinetic evaluation.
  • 5) In support of developing ideal dosing parameters for the Phase 2 clinical studies, the California CRO, Simulations Plus was utilized. ADMET Predictor™ was used to estimate the biopharmaceutical properties of APα. Predictive modeling of optimal dosing regimen and expected human exposure in Alzheimer’s patients was performed.
  • 6) Designed two Phase 2 clinical trials, a Multiple Ascending Dose (MAD) and a Proof of Concept. A California-based CRO, Worldwide Clinical Trials and Alzheimer's clinical trials expert were identified to partner with USC to design and conduct our clinical trials. Phase 2 MAD study primary objectives are to evaluate safety, tolerability and pharmacokinetics. MAD exploratory objectives are to evaluate effect of allopregnanolone on MRI biomarker outcomes and cognition. Proposed MRI biomarkers include hippocampal volume, white matter integrity, and functional connectivity. Phase 2 Proof of Concept trial primary objectives are to evaluate safety and tolerability with long-term exposure. Therapeutic efficacy of allopregnanolone will be determined by outcomes on cognition and biomarkers of regeneration in brain.
  • 7) A Steering Committee and Advisory Board were established. Both advisory groups are composed of internationally recognized researchers, translational scientists, regulatory experts and therapeutic development experts. The charge of the Steering Committee is to provide oversight that CIRM allopregnanolone team progress is on track to meet milestones, ensure that processes and strategies are aligned. The Advisory Board is comprised of internationally recognized experts in Alzheimer’s disease and experts in stem cell biology. Advisory Board members will provide an objective evaluation of CIRM allopregnanolone project progress. The functions of Advisory Board are: 1) Advise CIRM allopregnanolone project leadership on identifying key milestones; 2) Review progress on meeting milestones and hitting development targets; 3) Provide strategic and tactical counsel to the Leadership team and Steering Committee.
  • 8) Generated viable commercial potential through partnership with SAGE Therapeutics. Ensured patent progression and prosecution through USC. Engaged key opinion leaders in the field and educated these experts regarding therapeutic potential of allopregnanolone as a first in class drug for neuroregeneration in Alzheimer's disease.
Funding Type: 
Disease Team Therapy Planning I
Grant Number: 
DR2-05320
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$89 834
Disease Focus: 
Amyotrophic Lateral Sclerosis
Neurological Disorders
oldStatus: 
Closed
Public Abstract: 
This project aims to use a powerful combined stem cell and gene therapy approach to treat patients with amyotrophic lateral sclerosis (ALS or Lou Gehrig’s Disease). ALS is a devastating disease for which there is no treatment or cure. Progression from early muscle twitches to complete paralysis and death usually happens within 4 years. Every 90 minutes someone is diagnosed with ALS in the USA, and every 90 minutes someone dies from ALS. In California the death rate is one person every one and a half days. Stem cells have been shown to produce support cells for dying motor neurons called astrocytes which may slow down disease progression. Furthermore, many studies have shown that growth factors such as glial cell line-derived growth factor (or GDNF) can protect motor neurons from damage in a number of different animal models including those for ALS. However, delivering GDNF to the spinal cord has been almost impossible as it does not cross from the blood to the brain tissue. The idea behind the current proposal is to modify stem cells to produce GDNF and then transplant these cells into patients. A number of advances in human stem cell biology along with new surgical approaches has allowed us to put together this disease team approach – a first in man study to deliver cells modified to release a powerful growth factor that are expected to slow down the death of motor neurons and paralysis in patients. The focus of the proposal will be to perform essential preclinical studies in both small and large animals that will establish optimal doses and safe procedures for translating this stem cell and gene therapy into human patients. The Phase 1 clinical study will include 30 ALS patients from the state of California. This will be the first time this type of stem cell and gene therapy has been available to any ALS patients in the world.
Statement of Benefit to California: 
ALS is a devastating disease, and also puts a large burden on state resources through the need of full time care givers and hospital equipment. It is estimated that the cost of caring for an ALS patient in the late stage of disease while on a respiration is $200,00-300,000 per year. While primarily a humanitarian effort to avoid suffering, this project will also ease the cost of caring for ALS patients in California if ultimately successful. As the first trial in the world to combine stem cell and gene therapy it will make California a center of excellence for these types of studies. This in turn will attract scientists, clinicians, and companies interested in this area of medicine to the state of California thus increasing state revenue and state prestige in the rapidly growing field of Regenerative Medicine.
Progress Report: 
  • We completed the planning for submission of the CIRM Disease Team Grant on time. The series of meetings we had with leaders in the field of translational medicine as it relates to using stem cells secreting GDNF to treat ALS was extremely useful and allowed us to progress towards a very structured plan for both cell production, pre-clincial animal IND enabling studies and the final clinical trial involving 3 different institutions.
Funding Type: 
Disease Team Therapy Planning I
Grant Number: 
DR2-05272
Investigator: 
ICOC Funds Committed: 
$96 448
Disease Focus: 
Parkinson's Disease
Neurological Disorders
oldStatus: 
Closed
Public Abstract: 
We proposes to use human embryonic stem cells (hESCs) differentiated into neural progenitor/stem cells (NPCs), but modified by transiently programming the cells with the transcription factor MEF2C to drive them more specifically towards dopaminergic (DA) neurons, representing the cells lost in Parkinson’s disease. We will select Parkinson’s patients that no longer respond to L-DOPA and related therapy for our study, because no alternative treatment is currently available. The transplantation of cells that become DA neurons in the brain will create a population of cells that secrete dopamine, which may stop or slow the progression of the disease. In this way, moderate to severely affected Parkinson’s patients will benefit. The impact of development of a successful cell-based therapy for late-stage Parkinson’s patients would be very significant. There are approximately one million people in the United States with Parkinson’s disease (PD) and about ten million worldwide. Though L-DOPA therapy controls symptoms in many patients for a period of time, most reach a point where they fail to respond to this treatment. This is a very devastating time for sufferers and their families as the symptoms then become much worse. A cell-based therapy that restores production of dopamine and/or the ability to effectively use L-DOPA would greatly improve the lives of these patients. Because of our extensive preclinical experience and the clinical acumen of our Disease Team, we will be able to quickly adapt our procedures to human patients and be able to seek an IND from the FDA within four years.
Statement of Benefit to California: 
It is estimated that the cost per year for a Parkinson’s patient averages over $10,000 in direct costs and over $21,000 in total cost to society (in 2007 dollars). With nearly 40 million people in California and with one in 500 estimated to have Parkinson’s (1.5-2% of the population over 60 years of age), there are approximately 80,000 people in California with Parkinson’s disease. Thus, Parkinson’s disease is a significant burden to California, not to mention the devastating effect on those who have the disease and their families. A therapy that could halt the progression or reverse Parkinson’s disease would be of great benefit to the state and its residents. It would be particularly advantageous if the disease could be halted or reversed to an early stage, since the most severe symptoms and highest costs of care are associated with the late stages of the disease. Cell-based therapies offer the hope of achieving this goal.
Progress Report: 
  • A distinguished group of scientists was assembled by Dr. Stuart Lipton to plan a strategy to develop a human embryonic stem cell line expressing a constitutively active form of the transcription factor MEF2 (MEF2CA) into a therapeutic for treatment of Parkinson’s disease (PD), as funded by this planning grant. Preliminary data presented showed directed differentiation of the stem cells into mature dopaminergic cells and a positive outcome, histologically, electrophysiologically and behaviorally, when transplanted into a rat model. The salient features of the preliminary data show that the cells showed a strong propensity to differentiate into dopaminergic neurons, remaining endogenous dopaminergic neurons were saved from death or recruited to synthesize more dopamine through trophic interactions, and the behavioral readout showed that the rats’ neuromotor deficits were improved. An additional feature of the transplanted cells produced by the presented strategy was that none of the MEF2CA-expressing cells were hyperproliferative, indicating that tumor formation will not be a problem with their use. A strategy to further develop the cells under GMP conditions, test in rat and monkey models of PD and begin regulatory compliance for FDA approval was developed. Importantly, insertion of the Mef2CA gene in the stable stem cell line was verified by sequencing to occur at non-essential site of integration.

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