Neurological Disorders

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

Immune-Matched Neural Stem Cell Transplantation for Pediatric Neurodegenerative Disease

Funding Type: 
Early Translational III
Grant Number: 
TR3-05476
ICOC Funds Committed: 
$5 509 978
Disease Focus: 
Neurological Disorders
Pediatrics
Stem Cell Use: 
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.

Identifying Drugs for Alzheimer's Disease with Human Neurons Made From Human IPS cells

Funding Type: 
Early Translational III
Grant Number: 
TR3-05577
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.

Molecules to Correct Aberrant RNA Signature in Human Diseased Neurons

Funding Type: 
Early Translational III
Grant Number: 
TR3-05676
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.

Neural Stem Cell-Based Therapy For Parkinson’s Disease

Funding Type: 
Disease Team Therapy Planning I
Grant Number: 
DR2-05431
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.

A CIRM Disease Team to Develop Allopregnanolone for Prevention and Treatment of Alzheimer's Disease

Funding Type: 
Disease Team Therapy Planning I
Grant Number: 
DR2-05410
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.

Stem Cells Secreting GDNF for the Treatment of ALS

Funding Type: 
Disease Team Therapy Planning I
Grant Number: 
DR2-05320
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.

hESC-derived NPCs Programmed with MEF2C for Cell Transplantation in Parkinson’s Disease

Funding Type: 
Disease Team Therapy Planning I
Grant Number: 
DR2-05272
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.

Neuroprotection to treat Alzheimer's: a new paradigm using human central nervous system cells

Funding Type: 
Disease Team Therapy Planning I
Grant Number: 
DR2-05416
ICOC Funds Committed: 
$98 050
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
oldStatus: 
Closed
Public Abstract: 
Alzheimer’s disease (AD) is an incurable disorder that affects memory, social interaction and the ability to perform everyday activities. In the USA alone, the number of AD patients aged 65 and older has surpassed 5 million and that number may triple by 2050. Annual health care costs have been estimated to exceed 172 billion dollars, but do not reflect loss of income and stress caused to caregivers. Therefore, there is great hope for new therapies that will both improve symptoms and alleviate suffering. There are few FDA-approved medications to treat AD and none is capable of preventing, delaying onset or curing AD. Current medications mostly tend to temporarily slow the worsening of AD-associated symptoms such as sleep disturbances, depression and memory loss/disorientation. Pharmaceutical companies continue to develop new types of drugs or combination therapies that can better treat the symptoms or improve the quality of life of AD patients. There is also an ongoing effort to discover novel drugs that may prevent, reverse, or even cure AD. Unfortunately, the number of clinical studies addressing the possible benefit of such drugs is low, and agents that have shown initial promise have failed at later stage clinical testing, despite convincing preclinical data. There are ongoing studies in AD patients using vaccines and other biological compounds but it is unclear when data from these new trials will be available and more importantly, whether they will be successful. The need for divergent and innovative approaches to AD is clearly suggested by the failure of experimental drugs. Our proposal is to use brain stem cells to treat AD. This is a completely different approach to the more standard therapies described above such as drugs, vaccines, etc., and one that we hope will be beneficial for AD patients as a one-time intervention. AD is characterized by a dysfunction and eventual loss of neurons, the specialized cells that convey information in the brain. Death or dysfunction of neurons results in the characteristic memory loss, confusion and inability to solve new problems that AD patients experience. It is our hope that stem cells transplanted into the patient’s brain may provide factors that will protect neurons and preserve their function. Even a small improvement in memory and cognitive function could significantly alter quality of life in a patient with AD.
Statement of Benefit to California: 
Of the 5.4 million Americans affected with AD, 440,000 are California residents and, according to the Alzheimer’s Association, this number is projected to increase between 49.1 - 81.0% (second highest only to Northwestern states) between 2000 and 2025. Given that California is the most populous state, AD’s impact on state finances is proportionally high and will only increase as the population ages and AD incidence increases. The dementia resulting from this devastating disease disconnects patients from their community and loved ones by eroding memory and cognitive function. Patients gradually lose their ability to drive, work, cook and even carry out simple everyday tasks, and become totally dependent on others. The quality of life of AD patients is hugely affected and the burden on their families and caregivers is very costly to the state of California. There is no cure for AD and no way to prevent it. Most approved therapies only address symptomatic aspects of AD and disease modifying drugs are currently not available. By enacting Proposition 71, California voters acknowledged and supported the need to investigate the use of novel stem cell based therapies to treat currently incurable diseases such as AD. Our goal is to leverage our proven expertise in developing neural stem cell based therapies for human neurodegenerative disorders and apply it to AD. We propose that neural stem cell transplantation into select regions of the brain will have a beneficial impact on the patient. If successful, a single intervention may be sufficient to delay or stop progression of neuronal degeneration and preserve functional levels of cognition and memory. In a disease such as AD, any therapy that can exert even a modest impact on the patient’s ability to carry out some daily activities will have an exponential positive effect not only on patients but also on families, caregivers and the health care system. The potential economic impact of such type of therapeutic intervention for California could be tremendous, not only by reducing the high costs of care but also by becoming a vital world center for stem cell interventions in AD.
Progress Report: 
  • Alzheimer's disease (AD) is an incurable disorder that affects memory, social interaction, and the ability to perform everyday activities. The number of AD patients older than 65 has surpassed 5 million in the US and 600,000 in California, numbers that may triple by 2050. Annual health care costs related to AD have been estimated to exceed $172 billion in the US, even without reflecting either the loss of income or the physical and emotional stress experienced by caregivers. Efforts to discover novel and effective treatments for AD are ongoing, but unfortunately, the number of active clinical studies is low and many traditional approaches have failed in clinical testing. There is a great need for new therapies that will both improve symptoms and alleviate suffering.
  • AD is characterized by the dysfunction and eventual loss of neurons, the specialized cells that convey information in the brain. Death or dysfunction of neurons results in the characteristic memory loss, confusion, and inability to solve new problems that AD patients experience.
  • StemCells Inc. is embarking on an initiative to evaluate the use of its proprietary human neural stem cells to treat AD. We believe that neural stem cells transplanted into a patient’s brain may protect neurons and preserve their function. This represents an entirely new approach to standard therapeutic drug development for AD, which has so far resulted in drugs that only temporarily alleviate symptoms in some patients but that do not slow or change the course of the disease. We envision using neural stem cells as a one-time intervention that will improve memory and cognitive function in AD patients. Even a modest improvement in these symptoms could significantly alter the quality of life of a patient with AD.
  • StemCells Inc. received a Disease Team Planning (DTP) award from CIRM to establish a Disease Team for AD, and to begin organizing the activities required to submit a Disease Team Therapy Development (DTTD) award. We are reporting now on the successful completion of this DTP award. The main deliverables were (i) submission of a DTTD award application and (ii) development of a four year research plan that contemplates an Investigational New Drug (IND) submission to the FDA for the clinical study of neural stem cells in patients with AD, within four years.
  • To begin evaluating its proprietary human neural stem cells as a potential therapy for AD, StemCells Inc. and its collaborators from UC Irvine needed to first design IND-enabling safety and efficacy studies to test these stem cells in animal models relevant for AD. The DTP funding from CIRM helped support a series of telephone, email and face-to-face meetings over the last 6 months, between investigators at UCI and StemCells Inc., to present and evaluate existing data on neural stem cells and to share information about AD in order to design pilot and definitive efficacy and safety studies. During this time, the team also discussed the logistical details required to conduct these studies.
  • After a draft research plan had been outlined, StemCells Inc. and its principal collaborator at UCI, Dr. Frank LaFerla, enlisted the help of various experts in the field of AD, including both clinicians and academic scientists, to evaluate this plan. These experts attended a meeting at UCI and provided input into the experimental design of efficacy and safety studies. Many of these experts were also recruited by StemCells Inc. to participate in preclinical and clinical working groups hosted by the Company. These working groups will ultimately evaluate the preclinical experimental results and help design the protocol for the proposed clinical trial.
  • The DTP award also allowed StemCells Inc. to establish a “Project Team” consisting of highly trained and skilled personnel at UCI, StemCells Inc., and an established Contract Research Organization. This Project Team will be responsible for the production and supply of the human neural stem cells, the execution of all efficacy and safety studies, and the preparation and submission of IND documents to the FDA within the next 4 years.
  • Finally, the DTP award allowed StemCells Inc. to timely develop and submit its DTTD application to CIRM, in which the Company requested funding in the amount of up to $20 million to facilitate execution of IND-enabling safety and efficacy studies for its proposed breakthrough neural stem cell treatment for AD.

MSC engineered to produce BDNF for the treatment of Huntington's disease

Funding Type: 
Disease Team Therapy Planning I
Grant Number: 
DR2-05415
ICOC Funds Committed: 
$99 248
Disease Focus: 
Huntington's Disease
Neurological Disorders
oldStatus: 
Closed
Public Abstract: 
One in every ten thousand people in the USA has Huntington's disease, and it impacts many more. Multiple generations within a family can inherit the disease, resulting in escalating health care costs and draining family resources. This highly devastating and fatal disease touches all races and socioeconomic levels, and there are currently no cures. Screening for the mutant HD gene is available, but the at-risk children of an affected parent often do not wish to be tested since there are currently no early prevention strategies or effective treatments. We propose a novel therapy to treat HD; implantation of cells engineered to secrete Brain-Derived Neurotrophic factor (BDNF), a factor needed by neurons to remain alive and healthy, but which plummets to very low levels in HD patients due to interference by the mutant Huntingtin (htt) protein that is the hallmark of the disease. Intrastriatal implantation of mesenchymal stem cells (MSC) has significant neurorestorative effects and is safe in animal models. We have discovered that MSC are remarkably effective delivery vehicles, moving robustly through the tissue and infusing therapeutic molecules into each damaged cell that they contact. Thus we are utilizing nature's own paramedic system, but we are arming them with enhanced neurotrophic factor secretion to enhance the health of at-risk neurons. Our novel animal models will allow the therapy to be carefully tested in preparation for a phase 1 clinical trial of MSC/BDNF infusion into the brain tissue of HD patients, with the goal of restoring the health of neurons that have been damaged by the mutant htt protein. Delivery of BDNF by MSC into the brains of HD mice is safe and has resulted in a significant reduction in their behavioral deficits, nearly back to normal levels. We are doing further work to ensure that the proposed therapy will be safe and effective, in preparation for the phase 1 clinical trial. The significance of our studies is very high because there are currently no treatments to diminish the unrelenting decline in the numbers of medium spiny neurons in the striata of patients affected by HD. However this biological delivery system for BDNF could also be modified for other neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia (SCA1), Alzheimer's Disease, and some forms of Parkinson's Disease, where neuroregeneration is needed. Development of novel stem cell therapies is extremely important for the community of HD and neurodegenerative disease researchers, patients, and families. Since HD patients unfortunately have few other options, the benefit to risk ratio for the planned trial is very high.
Statement of Benefit to California: 
It is estimated that one in 10,000 CA residents have Huntington’s disease (HD). While the financial burden of HD is estimated to be in the billions, the emotional cost to friends, families, and those with or at risk for HD is immeasurable. Health care costs are extremely high for HD patients due to the long progression of the disease, often for two decades. The lost ability of HD patients to remain in the CA workforce, to support their families, and to pay taxes causes additional financial strain on the state’s economy. HD is inherited as an autosomal dominant trait, which means that 50% of the children of an HD patient will inherit the disease and will in turn pass it on to 50% of their children. Individuals diagnosed through genetic testing are at risk of losing insurance coverage in spite of reforms, and can be discriminated against for jobs, school, loans, or other applications. Since there are currently no cures or successful clinical trials to treat HD, many who are at risk are very reluctant to be tested. We are designing trials to treat HD through rescuing neurons in the earlier phases of the disease, before lives are devastated. Mesenchymal stem cells (MSC) have been shown to have significant effects on restoring synaptic connections between damaged neurons, promoting neurite outgrowth, secreting anti-apoptotic factors in the brain, and regulating inflammation. In addition to many trials that have assessed the safety and efficacy of human MSC delivery to tissues via systemic IV infusion, MSC are also under consideration for treatment of disorders in the CNS, although few MSC clinical trials have started so far with direct delivery to brain or spinal cord tissue. Therefore we are conducting detailed studies in support of clinical trials that will feature MSC implantation into the brain, to deliver the neurotrophic factor BDNF that is lacking in HD. MSC can be transferred from one donor to the next without tissue matching because they shelter themselves from the immune system. We have demonstrated the safe and effective production of engineered molecules from human MSC for at least 18 months, in pre-clinical animal studies, and have shown with our collaborators that delivery of BDNF can have significant effects on reducing disease progression in HD rodent models. We are developing a therapeutic strategy to treat HD, since the need is so acute. HD patient advocates are admirably among the most vocal in California about their desire for CIRM-funded cures, attending almost every public meeting of the governing board of the California Institute for Regenerative Medicine (CIRM). We are working carefully and intensely toward the first FDA-approved approved cellular therapy for HD patients which could have a major impact on those affected in California. In addition, the methods, preclinical testing models, and clincial trial design that we are developing could have far-reaching impact on the treatment of other neurodegenerative disorders.
Progress Report: 
  • A) Pre-clinical: The remainder of the IND-enabling studies were designed in consultation with Biologics Consulting Group (BCG). The project will begin with the IND-enabling phase and transition through regulatory approvals and through an observational trial and the Phase I clinical trial of stem cell therapy. The project has a Preclinical unit, under the leadership of co-PI Dr. Jan Nolta, and a Clinical unit, under the leadership of PI Dr. Vicki Wheelock. The two units are well integrated, since the team has been meeting weekly since 2009 to plan the testing of MSC trials for HD. During the planning phase we had a minimum of 4 hours of HD meetings per week, and worked continually on the project. This team is truly translational, with both PIs highly dedicated to this trial and motivated by the HD community.
  • Co-PI Jan Nolta, Ph.D. is Scientific Director of the UC Davis/CIRM GMP Facility, and will continue to direct ongoing IND-enabling studies for MSC/BDNF. The Pre-Clinical team will perform all IND-enabling studies at the level of GLP, and will manufacture and qualify the MSC and MSC/BDNF products in the GMP facility at UC Davis that is directed by Dr. Bauer (CMC lead). These studies are ongoing and we have been advised by BCG consulting lead Andra Miller, who was formerly Gene Therapy Group Leader at the FDA, CBER, Division of Cell and Gene Therapies, for almost a decade. BCG is assisting us with IND preparation.
  • Ms. Geralyn Annett is the experienced Project Manager. She is the UCD Stem Cell Program Manager and has worked in the field of academic and industry stem cell trials for 20+ years. She will oversee the regulatory team and keep the IND-enabling studies on task to meet the milestones. GMP Facility Director Gerhard Bauer will be responsible for regulatory filings with assistance from Dr. Nolta, the CMC team, and Dr. Miller. Dr. Nolta has worked on clinical trials of stem cell gene therapy, and associated translational studies with Ms. Annett and Director Bauer for over 20 years.
  • B) Clinical. The Clinical team is led by PI Dr. Vicki Wheelock, who is Director of the HDSA Center of Excellence at UC Davis and, with nurse practitioner Terry Tempkin, follows over 250 patients with HD in the UC Davis Movement Disorders clinic. The PI has extensive experience in conducting clinical trials and has already accrued HD patients to 14 clinical trials to date. The planning grant allowed us to conduct longer weekly meetings with different team members to complete planning of the proposed clinical trial.
  • Weekly HD meetings during the planning phase included PI Dr. Wheelock, Co-PI Dr. Nolta, Nurse practitioner Terry Tempkin, Program Manager Geralyn Annett, Psychiatrist Dr. Lorin Scher, Neuropsychologist Dr. Sarah Farias, Social Worker Lisa Kjer, and members of the Imaging Unit led by Dr. Charles DeCarli. This team has worked together on multiple clinical trials for HD patients. Some meetings additionally included Dr. Kiarash Shahlaie, the UCD functional neurosurgeon who will perform the targeting and surgical implantation of the cells, Dr. Bauer who directs the GMP facility (and his team members), the translational team who is performing the IND-enabling studies in Rodents (they usually meet separately for 2 hours/week with Dr. Nolta), and Dr. Tarantal who is leading the IND-enabling studies in non-human primates.
  • We met with our CRO, Paragon, who will be responsible for regulatory and safety filings including outcomes reports, medical and safety monitoring and management including DSMB, medical writing and quality assurance, clinical events committee- adjudicate AEs, and generate clinical study reports. Paragon will also oversee the development of the electronic case report forms, site management and monitoring, biostatistical analysis, and management of the database. We had on-site meetings and conference calls with Paragon during the planning Phase.
  • Additional meetings were conducted with collaborators and consultants:
  • A) Dunbar lab and Hersch lab in the US, both leaders in the HD field – for HD trial IND-enabling study research and HD mouse and patient biomarkers, respectively.
  • B) Aylward lab in the US for detailed brain imaging analyses in HD.
  • C) Paulsen lab for interpretation of cognitive assays in HD.
  • D) Phil Starr and Dan Lim at UCSF for ClearPoint cell injection system.
  • E) Bachoud-Levi lab in France for cell implantation in HD.
  • F) Dr. Robert (Willie) Mays and Bob Deans, Athersys – for IND-enabling studies/regulatory
  • In conclusion, the planning grant helped us to finalize plans for the proposed clinical trial and to complete our detailed plans for the remainder of the IND-enabling studies required to obtain FDA approval. These goals were accomplished through frequent meetings with key consultants and collaborators during the intense planning phase, where we completed the Disease Team application to CIRM that could potentially fund our proposed Phase I clinical trial of MSC/BDNF therapy for Huntington’s disease.

Evaluation of Safety and Preliminary Efficacy of Escalating Doses of GRNOPC1 in Subacute Spinal Cord Injury

Funding Type: 
Targeted Clinical Development
Grant Number: 
CT1-05168
ICOC Funds Committed: 
$24 846 856
Disease Focus: 
Spinal Cord Injury
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 
The proposed project is designed to assess the safety and preliminary activity of escalating doses of human embryonic stem cell (hESC) derived oligodendrocyte progenitor cells for treatment of spinal cord injury. Oligodendrocyte progenitor cells have two important functions: they produce neurotrophic factors which stimulate the survival and growth of neurons (nerve cells) after injury, and they mature in the spinal cord to produce myelin, the insulation which envelops neuronal axons (nerve cell bodies responsible for conduction) and facilitates unimpeded nerve impulse conduction. After extensive efficacy and safety testing, clinical testing of this product was initiated in 2010. Clinical testing is being initiated in paraplegic patients with neurologically complete thoracic injuries (i.e., those in which no motor or sensory function remains below the level of the injury). In the first cohort, a dose equivalent to the lowest efficacious dose observed in preclinical rodent studies is being administered. During the course of the proposed program, clinical safety studies testing increasing doses will be conducted. Upon demonstration of safety, clinical testing will be expanded to tetraplegic patients (complete cervical injuries) and to patients with incomplete thoracic injuries for additional safety testing. In each of the proposed studies, preliminary evidence of activity will be monitored using measures of improved neurological function and performance of daily living activities. The project plan also includes the manufacture of cells to be used in the clinical trials and additional supporting activities. By completion of the proposed project, we expect to have accumulated substantial safety data and preliminary efficacy data in three different patient subpopulations. This data will provide key information to inform the design and execution of advanced efficacy studies.
Statement of Benefit to California: 
The proposed project has the potential to benefit the state of California through 1) providing improved medical outcomes for patients with spinal cord injury and their families, 2) increasing California’s leadership in the emerging field of stem cell research, and 3) preserving and creating high quality, high paying jobs for Californians. Over 12,000 Americans suffer spinal cord injuries each year, and approximately 1.3 million people in the US are estimated to be living with spinal cord injuries. Although specific estimates for the state of California are not available, it is known that the majority of spinal cord injuries result from motor vehicle accidents, falls, acts of violence and recreational sporting activities, all of which are prevalent in California. Spinal cord injury affects not only the patient but family members, friends, healthcare workers and employers. It is estimated that one year after injury, only 11.6% of spinal cord injury patients are employed, and that spinal cord injuries cost $40.5 billion annually in the US. As the most populous state, California is disproportionately affected, negatively impacting our productivity, healthcare system and public finances. There are currently no approved therapies for the treatment of spinal cord injury. The product described in this application has initiated phase 1 clinical testing in patients with complete thoracic spinal cord injury. Even partial correction of any of the debilitating consequences of spinal cord injury could potentially enhance activities of daily living and increase employment while decreasing reliance on attendant care and subsequent medical interventions. California has a history of leadership in biotechnology, and is emerging as a leader in the development of stem cell therapeutics. Cutting edge stem cell research, in many cases funded by CIRM, is already underway in academic research laboratories and biotechnology companies throughout the state. The proposed project has the potential to further increase California’s leadership in the field of stem cell therapeutics through the performance of the first clinical testing of an hESC-derived therapy. The applicant has been located in California since its inception, and currently employs 182 full-time employees at its California headquarters with more than 50% of employees holding an advanced degree. These positions are highly skilled positions, offering competitive salaries and comprehensive benefits. The successful performance of the proposed project would enable significant additional jobs creation in preparation for pivotal trials and product registration.

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