Neurological Disorders

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

Restoration of memory in Alzheimer’s disease: a new paradigm using neural stem cell therapy

Funding Type: 
Disease Team Therapy Development - Research
Grant Number: 
DR2A-05416
ICOC Funds Committed: 
$20 000 000
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
Stem Cell Use: 
Adult Stem Cell
oldStatus: 
Active
Public Abstract: 
Alzheimer’s disease (AD), the leading cause of dementia, results in profound loss of memory and cognitive function, and ultimately death. In the US, someone develops AD every 69 seconds and there are over 5 million individuals suffering from AD, including approximately 600,000 Californians. Current treatments do not alter the disease course. The absence of effective therapies coupled with the sheer number of affected patients renders AD a medical disorder of unprecedented need and a public health concern of significant magnitude. In 2010, the global economic impact of dementias was estimated at $604 billion, a figure far beyond the costs of cancer or heart disease. These numbers do not reflect the devastating social and emotional tolls that AD inflicts upon patients and their families. 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. An urgent need to develop novel and innovative approaches to treat AD is clear. We propose to evaluate the use of human neural stem cells as a potential innovative therapy for AD. AD results in neuronal death and loss of connections between surviving neurons. The hippocampus, the part of the brain responsible for learning and memory, is particularly affected in AD, and is thought to underlie the memory problems AD patients encounter. Evidence from animal studies shows that transplanting human neural stem cells into the hippocampus improves memory, possibly by providing growth factors that protect neurons from degeneration. Translating this approach to humans could markedly restore memory and thus, quality of life for patients. The Disease Team has successfully initiated three clinical trials involving transplantation of human neural stem cells for neurological disorders. These trials have established that the cells proposed for this therapeutic approach are safe for transplantation into humans. The researchers in this Disease Team have shown that AD mice show a dramatic improvement in memory skills following both murine and human stem cell transplantation. With proof-of-concept established in these studies, the Disease Team intends to conduct the animal studies necessary to seek authorization by the FDA to start testing this therapeutic approach in human patients. This project will be conducted as a partnership between a biotechnology company with unique experience in clinical trials involving neural stem cell transplantation and a leading California-based academic laboratory specializing in AD research. The Disease Team also includes expert clinicians and scientists throughout California that will help guide the research project to clinical trials. The combination of all these resources will accelerate the research, and lead to a successful FDA submission to permit human testing of a novel approach for the treatment of AD; one that could enhance memory and save lives.
Statement of Benefit to California: 
The number of AD patients in the US has surpassed 5.4 million, and the incidence may triple by 2050. Roughly 1 out of every 10 patients with AD, over 550,000, is a California resident, and alarmingly, because of the large number of baby-boomers that reside in this state, the incidence is expected to more than double by 2025. Besides the personal impact of the diagnosis on the patient, the rising incidence of disease, both in the US and California, imperils the federal and state economy. The dementia induced by AD disconnects patients from their loved ones and communities by eroding memory and cognitive function. Patients gradually lose their ability to drive, work, cook, and carry out simple, everyday tasks, ultimately losing all independence. The quality of life for AD patients is hugely diminished and the burden on their families and caregivers is extremely costly to the state of California. Annual health care costs are estimated to exceed $172 billion, not including the additional costs resulting from the loss of income and physical and emotional stress experienced by caregivers of Alzheimer's patients. Given that California is the most populous state and the state with the highest number of baby-boomers, AD’s impact on California families and state finances is proportionally high and will only increase as the AD prevalence rises. Currently, there is no cure for AD and no means of prevention. Most approved therapies address only symptomatic aspects of AD and no disease-modifying approaches are currently available. By enacting Proposition 71, California voters acknowledged and supported the need to investigate the potential of novel stem cell-based therapies to treat diseases with a significant unmet medical need such as AD. In a disease like AD, any therapy that exerts even a modest impact on the patient's ability to carry out daily activities will have an exponential positive effect not only for the patients but also for their families, caregivers, and the entire health care system. We propose to evaluate the hypothesis that neural stem cell transplantation will delay the progression of AD by slowing or stabilizing loss of memory and related cognitive skills. A single, one-time intervention may be sufficient to delay progression of neuronal degeneration and preserve functional levels of memory and cognition; an approach that offers considerable cost-efficiency. The potential economic impact of this type of therapeutic research in California could be significant, and well worth the investment of this disease team proposal. Such an approach would not only reduce the high cost of care and improve the quality of life for patients, it would also make California an international leader in a pioneering approach to AD, yielding significant downstream economic benefits for the state.
Progress Report: 
  • Alzheimer’s disease (AD), the leading cause of dementia, results in profound loss of memory and cognitive function, and ultimately death. In the US, someone develops AD every 69 seconds and there are over 5 million individuals suffering from AD, including approximately 600,000 Californians. Current treatments do not alter the disease course. The absence of effective therapies coupled with the sheer number of affected patients renders AD a medical disorder of unprecedented need and a public health concern of significant magnitude. In 2010, the global economic impact of dementias was estimated at $604 billion, a figure far beyond the costs of cancer or heart disease. These numbers do not reflect the devastating social and emotional tolls that AD inflicts upon patients and their families. 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. An urgent need to develop novel and innovative approaches to treat AD is clear.
  • We have proposed to evaluate the use of human neural stem cells as a potential innovative therapy for AD. AD results in neuronal death and loss of connections between surviving neurons. The hippocampus, the part of the brain responsible for learning and memory, is particularly affected in AD, and is thought to underlie the memory problems AD patients encounter. Evidence from previous animal studies shows that transplanting human neural stem cells into the hippocampus improves memory, possibly by providing growth factors that protect neurons from degeneration. Translating this approach to humans could markedly restore memory and thus, quality of life for patients.
  • In the first year of the loan, the Disease Team actively worked on 5 important milestones in our effort to develop the use of human neural stem cells for AD. Of those, 2 milestones have been completed and 3 are ongoing. Specifically, the team has initiated three animal studies believed necessary to seek authorization by the FDA to start testing this therapeutic approach in human patients; these studies were designed to confirm that transplantation of the neural stem cells leads to improved memory in animal models relevant for AD. We are currently collecting and analyzing the data generated in these mouse studies. We have also identified the neural stem cell line that will be used in patients and have made considerable progress in its manufacturing and banking. Finally, we have held a pre-IND meeting with the FDA in which we shared our plans for the preclinical and clinical studies; the meeting provided helpful guidance and assurances regarding our IND enabling activities.
  • This project is a partnership between a biotechnology company with unique experience in clinical trials involving neural stem cell transplantation and a leading California-based academic laboratory specializing in AD research. Together with expert clinicians and scientists throughout California, we continue to work towards a successful IND submission to permit human testing of a novel and unique approach for the treatment of AD.

Developing a regeneration-based functional restoration treatment for spinal cord injury

Funding Type: 
Research Leadership 7
Grant Number: 
LA1_C7-05735
ICOC Funds Committed: 
$5 609 890
Disease Focus: 
Spinal Cord Injury
Neurological Disorders
oldStatus: 
Closed
Public Abstract: 
One of the most exciting and challenging frontiers in neuroscience and medicine is to repair traumatic injuries to the central nervous system (CNS). Most spinal cord and head injuries result in devastating paralyses, yet very limited clinical intervention is currently available to restore the lost abilities. Traumatic injuries of the spine cause fractures and compression of the vertebrae, which in turn crush and destroy the axons, long processes of nerve cells that carry signals up and down the spinal cord between the brain and the rest of the body. It follows that the best chance for promoting functional recovery is identifying strategies that enable lesioned axons to regenerate and reconnect the severed neural circuits. Even minor improvements in voluntary motor functions after spinal cord injury could be immensely helpful for increasing the quality of life, employability, and independence, especially for patients with injuries at the upper spinal level. Thus, our overall research program centers on axon regeneration in general, with a focus on regenerating descending axons from the brain that control voluntary motor and other functions. We recently made breakthrough discoveries in identifying key biological mechanisms stimulating the re-growth of injured axons in the adult nervous system, which led to unprecedented extents of axon regeneration in various CNS injury models. While our success was compelling, we found that many regenerated axons were stalled at the lesion sites by the injury-induced glial scars. Furthermore, it is unclear whether the regenerated axons can form functional synaptic connections when they grow into the denervated spinal cord. This proposed research program is aimed at solving these obstacles by using human stem cell technologies. In the first aim, we will use human neural stem cells to engineer “permissive cell bridges” that can guide the maximum number of regenerating axons to grow across injury sites. In the second aim, we will test the therapeutic potential of human stem cell-derived neurons in forming “functional relays” that could propagate the brain-derived signals carried by regenerating axons to the injured spinal cord. Together, our research program is expected to develop a set of therapeutic strategies that have immediate clinical implications for human SCI patients.
Statement of Benefit to California: 
Approximately 1.9% of the U.S. population, roughly 5,596,000 people, report some forms of paralysis; among whom, about 1,275,000 individuals are paralyzed due to spinal cord injuries (SCI). The disabilities and medical complications associated with SCI not only severely reduce the quality of life for the injured individuals, but also result in an estimated economical burden of $400,000,000 annually for the state of California in lost productivity and medical expenses. Traumatic injuries of the spine cause fractures and compression of the vertebrae, which in turn crush and destroy the axons, long processes of nerve cells that carry signals up and down the spinal cord between the brain and the rest of the body. Thus, identifying strategies that enable lesioned axons to regenerate and reconnect the severed neural circuits is crucial for promoting functional recovery after SCI. In recent years, we made breakthrough discoveries in identifying key biological mechanisms stimulating the re-growth of injured axons in the adult nervous system. This proposed research program is aimed at developing human neural stem cell based therapeutic strategies that enable regenerated axons to grow through tissue cavities at the injury site, and establish functionally relays between the regenerating cortical axons and the spinal circuits below the injury site, thereby restore the lost sensory/motor functions in SCI patients. Success of these proposed studies could lead to immediate therapeutic applications for SCI patients. The first stem cell-based clinical trial for human SCI is started in California in which stem cells are used to provide support and stimulate remyelination. Our stem cell based therapeutic strategies are aimed at re-building neural connections, which will compliment the existing strategy nicely. As a result, Californians will be the first beneficiaries of these therapies.

Functional Neural Relay Formation by Human Neural Stem Cell Grafting in Spinal Cord Injury

Funding Type: 
Early Translational III
Grant Number: 
TR3-05628
ICOC Funds Committed: 
$4 699 569
Disease Focus: 
Spinal Cord Injury
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 
We aim to develop a novel stem cell treatment for spinal cord injury (SCI) that is substantially more potent than previous stem cell treatments. By combining grafts of neural stem cells with scaffolds placed in injury sites, we have been able to optimize graft survival and filling of the injury site. Grafted cells extend long distance connections with the injured spinal cord above and below the lesion, while the host spinal cord also sends inputs to the neural stem cell implants. As a result, new functional relays are formed across the lesion site. These result in substantially greater functional improvement than previously reported in animal studies of stem cell treatment. Work proposed in this grant will identify the optimal human neural stem cells for preclinical development. Furthermore, in an unprecedented step in spinal cord injury research, we will test this treatment in appropriate preclinical models of SCI to provide the greatest degree of validation for human translation. Successful findings could lead to clinical trials of the most potent neural stem cell approach to date.
Statement of Benefit to California: 
Spinal cord injury (SCI) affects approximately 1.2 million people in the United States, and there are more than 11,000 new injuries per year. A large number of spinal cord injured individuals live in California, generating annual State costs in the billions of dollars. This research will examine a novel stem cell treatment for SCI that could result in functional improvement, greater independence and improved life styles for injured individuals. Results of animal testing of this approach to date demonstrate far greater functional benefits than previous stem cell therapies. We will generate neural stem cells from GMP-compatible human embryonic stem cells, then test them in the most clinically relevant animal models of SCI. These studies will be performed as a multi-center collaborative effort with several academic institutions throughout California. In addition, we will leverage expertise and resources currently in use for another CIRM-funded project for ALS, thereby conserving State resources. If successful, these studies will form the basis for clinical trials in a disease of great unmet medical need, spinal cord injury. Moreover, the development of this therapy would reduce costs for clinical care while bringing novel biomedical resources to the State.
Progress Report: 
  • In the first 12 months of this project we have made important progress in the following areas:
  • 1) Identified the lead embryonic stem cell type for potential use in a translational clinical program.
  • 2) Replicated the finding that implants of ES-derived neural progenitor cells from this lead cell type extend axons out from the spinal cord lesion site in very high numbers and over very long distances.
  • 3) Begun efforts to scale this work to larger animal models of spinal cord injury.

Human ES cell-derived MGE inhibitory interneuron transplantation for spinal cord injury

Funding Type: 
Early Translational III
Grant Number: 
TR3-05606
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.

Multiple Sclerosis therapy: Human Pluripotent Stem Cell-Derived Neural Progenitor Cells

Funding Type: 
Early Translational III
Grant Number: 
TR3-05603
ICOC Funds Committed: 
$4 799 814
Disease Focus: 
Multiple Sclerosis
Neurological Disorders
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.

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.

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