Neurological Disorders

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

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

Funding Type: 
Disease Team Therapy Development - Research
Grant Number: 
DR2A-05415
ICOC Funds Committed: 
$18 950 061
Disease Focus: 
Huntington's Disease
Neurological Disorders
Stem Cell Use: 
Adult Stem Cell
Cell Line Generation: 
Adult Stem Cell
oldStatus: 
Active
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 I 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 I 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. Our 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 potential 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 planned 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 clinical trial design that we are developing could have far-reaching impact on the treatment of other neurodegenerative disorders.
Progress Report: 
  • Huntington’s disease (HD) is a hereditary, fatal neuropsychiatric disease. HD occurs in one in every ten thousand people in the USA. The effects of the disease on patients, families, and care givers are devastating as it reaches from generation to generation. This fatal disease touches all races and socioeconomic levels, and current treatment is strictly palliative. Existing drugs can reduce the involuntary movements and psychiatric symptoms, but do nothing to slow the inexorable progression. There is currently no cure for HD. People at risk of inheriting HD can undergo a genetic counseling and testing to learn if they are destined to develop this dreadful disease. Many people from HD families fear the consequences of stigma and genetic discrimination. Those at-risk often do not choose 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 that can promote addition of new neurons to the affected area of the brain. BDNF is reduced in HD patients due to interference by the mutant Huntingtin (htt) protein that is the hallmark of the disease. We have discovered that mesenchymal stem/stromal cells (MSC), a type of adult stem cell, are remarkably effective delivery vehicles, moving robustly through the tissue and infusing therapeutic molecules into damaged cells they contact. In animal models of HD implantation of MSC into the brain has significant neurorestorative effects and is safe. We propose to use these MSCs as “nature's own paramedic system”, arming them with BDNF to enhance the health of at-risk neurons. Our HD animal models will allow the therapy to be carefully tested in preparation for a proposed Phase I clinical trial of MSC/BDNF implantation into the brain of HD patients (HD-CELL), with the goal of slowing disease progression.
  • 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 efficacy and safety studies in preparation for the Phase I clinical trial. The significance of our studies is very high because there are currently no other options, there is no current treatment to delay the onset or slow the progression of the disease.. There are potential applications beyond Huntington’s disease. Our biological delivery system for BDNF sets the precedent for adult stem cell therapy in the brain and could potentially be modified for other neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia (SCA), Alzheimer's disease, and some forms of Parkinson's disease. Since HD patients unfortunately have few other options, the potential benefit to risk ratio for the planned trial is very high.
  • In the first year of our grant we have successfully engineered human MSCs to produce BDNF, and are studying effects on disease progression in HD mice. We have developed methods to produce these cells in large quantities to be used for future human clinical studies. As we go forward in year 2 we plan to complete the animal studies that will allow us to apply for regulatory approval to go forward with the planned Phase I trial.
  • We have designed an observational study, PRE-CELL, to track disease progression and generate useful data in preparation for this future planned Phase I clinical trial. PRE-CELL has been approved by the institution’s ethics board and is currently enrolling subjects. PRE-CELL was designed to operate concurrently with the ongoing pre-clinical safety testing. For additional information go to: ClinicalTrials.gov Identifier: NCT01937923

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.

Neural restricted, FAC-sorted, human neural stem cells to treat traumatic brain injury

Funding Type: 
Early Translational II
Grant Number: 
TR2-01767
ICOC Funds Committed: 
$1 708 549
Disease Focus: 
Neurological Disorders
Trauma
Collaborative Funder: 
Maryland
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 
Traumatic brain injury (TBI) affects 1.4 million Americans a year; 175,000 in California. When the brain is injured, nerve cells near the site of injury die due to the initial trauma and interruption of blood flow. Secondary damage occurs as neighboring tissue is injured by the inflammatory response to the initial injury, leading to a larger area of damage. This damage happens to both neurons, the electrically active cells, and oligodendrocytes, the cell which makes the myelin insulation. A TBI patient typically loses cognitive function in one or more domains associated with the damage (e.g. attention deficits with frontal damage, or learning and memory deficits associated with temporal lobe/hippocampal damage); post-traumatic seizures are also common. Currently, no treatments have been shown to be beneficial in alleviating the cognitive problems following even a mild TBI. Neural stem cells (NSCs) provide a cell population that is promising as a therapeutic for neurotrauma. One idea is that transplanting NSCs into an injury would provide “cell replacement”; the stem cells would differentiate into new neurons and new oligodendrocytes and fill in for lost host cells. We have successfully used “sorted“ human NSCs in rodent models of spinal cord injury, showing that hNSCs migrate, proliferate, differentiate into oligodendrocytes and neurons, integrate with the host, and restore locomotor function. Killing the NSCs abolishes functional improvements, showing that integration of hNSCs mediates recovery. Two Phase I FDA trials support the potential of using sorted hNSC for brain therapy and were partially supported by studies in my lab. NSCs may also improve outcome by helping the host tissue repair itself, or by providing trophic support for newly born neurons following injury. Recently, transplantation of rodent-derived NSCs into a model of TBI showed limited, but significant improvements in some outcome measures. These results argue for the need to develop human-derived NSCs that can be used for TBI. We will establish and characterize multiple “sorted” and “non-sorted“ human NSC lines starting from 3 human ES lines. We will determine their neural potential in cell culture, and use the best 2 lines in an animal model of TBI, measuring learning, memory and seizure activity following TBI; then correlating these outcomes to tissue modifying effects. Ultimately, the proposed work may generate one or more human NSC lines suitable to use for TBI and/or other CNS injuries or disorders. A small reduction in the size of the injury or restoration of just some nerve fibers to their targets beyond the injury could have significant implications for a patient’s quality of life and considerable economic impact to the people of California. If successful over the 3-year grant, additional funding of this approach may enable a clinical trial within the next five years given success in the Phase I FDA approved trials of sorted hNSCs for other nervous system disorders.
Statement of Benefit to California: 
The Centers for Disease Control and Prevention estimate that traumatic brain injury (TBI) affects 1.4 million Americans every year. This equates to ~175,000 Californian’s suffering a TBI each year. Additionally, at least 5.3 million Americans currently have a long-term or a lifelong need for help to perform activities of daily living as a result of suffering a TBI previously. Forty percent of patients who are hospitalized with a TBI had at least one unmet need for services one year after their injury. One example is a need to improve their memory and problem solving skills. TBI can also cause epilepsy and increases the risk for conditions such as Alzheimer's disease, Parkinson's disease, and other brain disorders that become more prevalent with age. The combined direct medical costs and indirect costs such as lost productivity due to TBI totaled an estimated $60 billion in the United States in 2000 (when the most recent data was available). This translates to ~$7.5 billion in costs each year just to Californians. The proposed research seeks to generate several human neural-restricted stem cell lines from ES cells. These “sorted” neural-restricted stem cell lines should have greatly reduced or no tumor forming capability, making them ideally suited for clinical use. After verifying that these lines are multipotent (e.g. they can make neurons, astrocytes and oligodendrocytes), we will test their efficacy to improve outcomes in TBI on a number of measures, including learning and memory, seizure activity, tissue sparing, preservation of host neurons, and improvements in white matter pathology. Of benefit to California is that these same outcome measures in a rodent model of TBI can also be assessed in humans with TBI, potentially speeding the translational from laboratory to clinical application. A small reduction in the size of the injury, or restoration of just some nerve fibers to their targets beyond the injury, or moderate improvement in learning and memory post-TBI, or a reduction in the number or severity of seizures could have significant implications for a patient’s quality of life and considerable economic impact to the people of California. Additionally, the cell lines we have chosen to work with are unencumbered with IP issues that would prevent us, or others, from using these cell lines to test in other central nervous system disorders. Two of the cell lines have already been manufactured to “GMP” standards, which would speed up the translation of this work from the laboratory to the clinic. Finally, if successful, these lines would be potentially useful for treating a variety of central nervous system disorders in addition to TBI, including Alzheimer’s disease, Parkinson’s disease, stroke, autism, spinal cord injury, and/or multiple sclerosis.
Progress Report: 
  • In the first year of this Early Translation Award for traumatic brain injury (TBI), our goal was to develop the stem cells lines necessary to begin testing of stem cells in an animal model of TBI in year 2. If we are fortunate to demonstrate that the stem cell products are effective in animal models of TBI, these cells will need to be grown in a way that is acceptable to the FDA for future use in man. Xenofree means that the cells are not exposed to possible animal product contaminants (e.g. serum or blood products) and that every component that the cells were exposed to is chemically defined and can be traced to the original source.
  • First, we obtained three separate embryonic stem (ES) cell lines from Sheffield, UK and imported them to the United States. These lines where then thawed and grown in “xenofree” cell culture conditions. Many labs have had difficulty transitioning human ES cells to xenofree conditions without introducing genetic defects in the cell lines or killing the cells. We were able to work out the correct conditions for all three ES cell lines to be grown xenofree. We were also successful in converting two of the three ES lines into neural stem cells (the subtype of stem cell needed for transplanting into brain tissue). These neural stem cells (NSCs) were further purified by labeling them for a stem cell surface marker present on NSCs (called CD133) and then magnetically sorting out just the CD133 positive cells and continuing to grow them. This approach is thought to enrich the stem cell population for NSCs and eliminate any remaining non-differentiated ES cells (which have an added risk of forming tumors if injected into animals or man). We successfully “sorted” both Shef cell lines and we now have four candidate populations of sorted and unsorted Shef4 and Shef6 cells. We grew these cells in culture and tested whether they differentiated into neuronal precursor or glial precursor cells. Quantification of the type of cells they turn into after 2 weeks showed that the four cell populations were different. These differences were even more apparent when looking at the cells in a microscope. At the end of year one, we have four different populations of neural stem cells which are growing in defined xenofree conditions, are frozen down in master cell banks, and which are genetically normal. There are sufficient quantities of these human neural stem cells (hNSC) to complete the remaining aims of the ETA grant over the remaining two years.
  • In the first year we also trained staff in the surgical procedures required to produce controlled cortical impact injuries in Athymic nude rats (ATNs), a type of rat that has no immune system. These procedures were necessary because no one has ever used ATN rats to model TBI. Our goal in year two is to transplant hNSCs into rats with TBI. If the rats had a normal immune system, their bodies would detect the foreign human cells and reject them. Also, because no one has ever tested TBI in ATN rats, we needed to find out if ATN rats respond like regular rats to the injury and if they have similar, predictable deficits on the cognitive tasks we plan to use in year 2 to measure whether hNCSs improve the animal’s recovery or not. This training and these pilot tests in ATN rats were completed successfully. Finally, the hypothesis is that by “sorting” the hNSCs to be CD133 positive, we are making the stem cell population safer for transplantation. This will be tested in year 2 using a tumorigenicity assay. We worked out how to conduct these assays in year 1 using a population of ES cells known to cause tumors so that we will have a positive control to compare the hNSCs to in year 2.
  • In summary, we met all of our goals and milestones for year 1 and are poised to make good progress in year 2.
  • The goal of this project is to take three human embryonic stem cell lines (Shef3, Shef4, and Shef6), transition them to multipotent neural stem cell (hNSC) populations, sort/enrich these hNSC stem/progenitor populations, and then test these cell lines for efficacy in a rat model of controlled cortical impact (CCI) model of traumatic brain injury (TBI). Our strategy is to develop xenofree culture methods for the transition of hESC to NSCs, use magnetic activated cell sorting (MAC) for the cell surface markers CD133+/CD34- to enrich the hNSC populations for stem/progenitor cells, test these sorted vs unsorted cell lines in tumorigenicity assays, and use the best two non-tumorigenic lines in a CCI model of TBI. Efficacy will be assessed on a battery of cognitive tests, via a reduction in spontaneous seizure, and in histological outcomes.
  • At the Two Year time-point in the grant, we have (A) generated 6 hNSC populations, (B) completed short-term teratoma assays which demonstrate that none of our hNSC populations form teratomas in either of two transplantation sites (sub cutaneous into the leg or intracranially into the brain, (C) established parameters for graded contusion traumatic brain injuries in ATN rats that (D) yield long-term (≥8 weeks) deficits in both learning and memory on the Morris Water Maze. (E) We have also determined that TBI yields an altered response on a conditioned taste aversion task (neophobia) and on the elevated plus maze compared to sham controls. (F) Determined that unsorted hNSCs (both Shef4 and Shef6) do not survive long-term in uninjured brain and (G) transplanted two large cohorts of TBI injured animals with Shef6 sorted NSCs of high passage, Shef6 sorted hNSCs of low passage, sham animals, and animals with a vehicle control. These two cohorts are too large to run simultaneously, so they are being run in parallel. Animals from both cohorts will complete functional all assessments by the end of June 2013.
  • Summary: We have very promising preclinical efficacy data in a rodent model of traumatic brain injury (TBI) using stem cells as a potential therapeutic. We have found that intra-cranial transplants of Shef-6 derived human neural stem cells (hNSCs) appear to induce improvement on two different behavioral domains after long-term (>2 months) survival. Importantly, Shef-6 hNSCs did not form tumors when transplanted at high doses into naïve brain. Shef-6 hNSCs are xenofree, GMP compatible, suitable for use in man (the donor and cells were certified to be free of HIV, Hepatitis A, B, C, HTLV, EBV, CMV, and are mycoplasma free). Furthermore, Shef-6 is on the FDA embryonic stem cell registry, enabling future Federal funding of their clinical testing in man if warranted. Specifically, we have demonstrated long-term efficacy in a moderate to severe controlled cortical impact (CCI) model of TBI using Shef-6 derived hNSCs on both a cognitive task (MWM Reversal Learning) and an emotional task (Elevated Plus Maze for anxiety). This dual improvement across cognitive and emotional domains is unique to the field and supports external validity of the model. These behavioral findings need to be correlated with quantification of the total number of surviving human cells and their terminal cell fate (whether the hNSCs differentiated into neurons, oligodendrocytes, or astrocytes) to confirm efficacy. Stereological quantification is currently ongoing and very labor intensive. If the correlation between surviving cells and cognitive improvements holds up after the quantification is complete, these findings will support a future Preclinical Development Award application to CIRM. Additionally, we are the first group to couple kindling and TBI to model the critical complication of post-TBI seizures. Traditional TBI models yield seizures in less than 20% of rodents, making hNSC studies cost prohibitive. Coupling kindling with TBI ensures that all animals start with a hypersensitive neural circuit so hNSCs can be tested in a more relevant environment; we will be ready to begin this important kindling test coupled with hNSCs in the Spring of 2014. These studies have paved new ground for a field with huge economic costs, no treatments, and no GMP qualified ES based solutions on the horizon.

Enhancing healing via Wnt-protein mediated activation of endogenous stem cells

Funding Type: 
Early Translational I
Grant Number: 
TR1-01249
ICOC Funds Committed: 
$6 762 954
Disease Focus: 
Bone or Cartilage Disease
Heart Disease
Neurological Disorders
Stroke
Skin Disease
Stem Cell Use: 
Adult Stem Cell
oldStatus: 
Active
Public Abstract: 
All adult tissues contain stem cells. Some tissues, like bone marrow and skin, harbor more adult stem cells; other tissues, like muscle, have fewer. When a tissue or organ is injured these stem cells possess a remarkable ability to divide and multiply. In the end, the ability of a tissue to repair itself seems to depend on how many stem cells reside in a particular tissue, and the state of those stem cells. For example, stress, disease, and aging all diminish the capacity of adult stem cells to self-renew and to proliferate, which in turn hinders tissue regeneration. Our strategy is to commandeer the molecular machinery responsible for adult stem cell self-renewal and proliferation and by doing so, stimulate the endogenous program of tissue regeneration. This approach takes advantage of the solution that Nature itself developed for repairing damaged or diseased tissues, and controls adult stem cell proliferation in a localized, highly controlled fashion. This strategy circumvents the immunological, medical, and ethical hurdles that exist when exogenous stem cells are introduced into a human. When utilizing this strategy the goal of reaching clinical trials in human patients within 5 years becomes realistic. Specifically, we will target the growing problem of neurologic, musculoskeletal, cardiovascular, and wound healing diseases by local delivery of a protein that promotes the body’s inherent ability to repair and regenerate tissues. We have evidence that this class of proteins, when delivered locally to an injury site, is able to stimulate adult tissue stem cells to grow and repair/replace the deficient tissue following injury. We have developed technologies to package the protein in a specialized manner that preserves its biological activity but simultaneously restricts its diffusion to unintended regions of the body. For example, when we treat a skeletal injury with this packaged protein we augment the natural ability to heal bone by 350%; and when this protein is delivered to the heart immediately after an infarction cardiac output is improved and complications related to scarring are reduced. This remarkable capacity to augment tissue healing is not limited to bones and the heart: the same powerful effect can be elicited in the brain, and skin injuries. The disease targets of stroke, bone fractures, heart attacks, and skin wounds and ulcers represent an enormous health care burden now, but this burden is expected to skyrocket because our population is quickly aging. Thus, our proposal addresses a present and ongoing challenge to healthcare for the majority of Californians, with a novel therapeutic strategy that mimics the body’s inherent repair mechanisms.
Statement of Benefit to California: 
Californians represent 1 in 7 Americans, and make up the single largest healthcare market in the United States. The diseases and injuries that affect Californians affect the rest of the US, and the world. For example, stroke is the third leading cause of death, with more than 700,000 people affected every year. It is a leading cause of serious long-term disability, with an estimated 5.4 million stroke survivors currently alive today. Symptoms of musculoskeletal disease are the number two most cited reasons for visit to a physician. Musculoskeletal disease is the leading cause of work-related and physical disability in the United States, with arthritis being the leading chronic condition reported by the elderly. In adults over the age of 70, 40% suffer from osteoarthritis of the knee and of these nearly 80% have limitation of movement. By 2030, nearly 67 million US adults will be diagnosed with arthritis. Cardiovascular disease is the leading cause of death, and is a major cause of disability worldwide. The annual socioeconomic burden posed by cardiovascular disease is estimated to exceed $400 billion annually and remains a major cause of health disparities and rising health care costs. Skin wounds from burns, trauma, or surgery, and chronic wounds associated with diabetes or pressure ulcer, exact a staggering toll on our healthcare system: Burns alone affect 1.25M Americans each year, and the economic global burden of these injuries approaches $50B/yr. In California alone, the annual healthcare expenditures for stroke, skeletal repair, heart attacks, and skin wound healing are staggering and exceed 700,000 cases, 3.5M hospital days, and $34B. We have developed a novel, protein-based therapeutic platform to accelerate and enhance tissue regeneration through activation of adult stem cells. This technology takes advantage of a powerful stem cell factor that is essential for the development and repair of most of the body’s tissues. We have generated the first stable, biologically active recombinant Wnt pathway agonist, and showed that this protein has the ability to activate adult stem cells after tissue injury. Thus, our developmental candidate leverages the body’s natural response to injury. We have generated exciting preclinical results in a variety of animals models including stroke, skeletal repair, heart attack, and skin wounding. If successful, this early translational award would have enormous benefits for the citizens of California and beyond.
Progress Report: 
  • In the first year of CIRM funding our objectives were to optimize the activity of the Wnt protein for use in the body and then to test, in a variety of injury models, the effects of this lipid-packaged form of Wnt. We have made considerable progress on both of these fronts. For example, in Roel Nusse and Jill Helms’ groups, we have been able to generate large amounts of the mouse form of Wnt3a protein and package it into liposomal vesicles, which can then be used by all investigators in their studies of injury and repair. Also, Roel Nusse succeeded in generating human Wnt3a protein. This is a major accomplishment since our ultimate goal is to develop this regenerative medicine tool for use in humans. In Jill Helms’ lab we made steady progress in standardizing the activity of the liposomal Wnt3a formulation, and this is critically important for all subsequent studies that will compare the efficacy of this treatment across multiple injury repair scenarios.
  • Each group began testing the effects of liposomal Wnt3a treatment for their particular application. For example, in Theo Palmer’s group, the investigators tested how liposomal Wnt3a affected cells in the brain following a stroke. We previously found that Wnt3A promotes the growth of neural stem cells in a petri dish and we are now trying to determine if delivery of Wnt3A can enhance the activity of endogenous stem cells in the brain and improve the level of recovery following stroke. Research in the first year examined toxicity of a liposome formulation used to deliver Wnt3a and we found it to be well tolerated after injection into the brains of mice. We also find that liposomal Wnt3a can promote the production of new neurons following stroke. The ongoing research involves experiments to determine if these changes in stem cell activity are accompanied by improved neurological function. In Jill Helms’ group, the investigators tested how liposomal Wnt3a affected cells in a bone injury site. We made a significant discovery this year, by demonstrating that liposomal Wnt3a stimulates the proliferation of skeletal progenitor cells and accelerates their differentiation into osteoblasts (published in Science Translational Medicine 2010). We also started testing liposomal Wnt3a for safety and toxicity issues, both of which are important prerequisites for use of liposomal Wnt3a in humans. Following a heart attack (i.e., myocardial infarction) we found that endogenous Wnt signaling peaks between post-infarct day 5-7. We also found that small aggregates of cardiac cells called cardiospheres respond to Wnt in a dose-responsive manner. In skin wounds, we tested the effect of boosting Wnt signaling during skin wound healing. We found that the injection of Wnt liposomes into wounds enhanced the regeneration of hair follicles, which would otherwise not regenerate and make a scar instead. The speed and strength of wound closure are now being measured.
  • In aggregate, our work on this project continues to move forward with a number of great successes, and encouraging data to support our hypothesis that augmenting Wnt signaling following tissue injury will provide beneficial effects.
  • In the second year of CIRM funding our objectives were to optimize packaging of the developmental candidate, Wnt3a protein, and then to continue to test its efficacy to enhance tissue healing. We continue to make considerable progress on the stated objectives. In Roel Nusse’s laboratory, human Wnt3a protein is now being produced using an FDA-approved cell line, and Jill Helms’ lab the protein is effectively packaged into lipid particles that delay degradation of the protein when it is introduced into the body.
  • Each group has continued to test the effects of liposomal Wnt3a treatment for their particular application. In Theo Palmer’s group we have studied how liposomal Wnt3a affects neurogenesis following stroke. We now know that liposomal Wnt3a transiently stimulates neural progenitor cell proliferation. We don’t see any functional improvement after stroke, though, which is our primary objective.
  • In Jill Helms’ group we’ve now shown that liposomal Wnt3a enhances fracture healing and osseointegration of dental and orthopedic implants and now we demonstrate that liposomal Wnt3a also can improve the bone-forming capacity of bone marrow grafts, especially when they are taken from aged animals.
  • We’ve also tested the ability of liposomal Wnt3a to improve heart function after a heart attack (i.e., myocardial infarction). Small aggregates of cardiac progenitor cells called cardiospheres proliferate to Wnt3a in a dose-responsive manner, and we see an initial improvement in cardiac function after treatment of cells with liposomal Wnt3a. the long-term improvements, however, are not significant and this remains our ultimate goal. In skin wounds, we tested the effect of boosting Wnt signaling during wound healing. We found that the injection of liposomal Wnt3a into wounds enhanced the regeneration of hair follicles, which would otherwise not regenerate and make a scar instead. The speed of wound closure is also enhanced in regions of the skin where there are hair follicles.
  • In aggregate, our work continues to move forward with a number of critical successes, and encouraging data to support our hypothesis that augmenting Wnt signaling following tissue injury will provide beneficial effects.
  • Every adult tissue harbors stem cells. Some tissues, like bone marrow and skin, have more adult stem cells and other tissues, like muscle or brain, have fewer. When a tissue is injured, these stem cells divide and multiply but only to a limited extent. In the end, the ability of a tissue to repair itself seems to depend on how many stem cells reside in a particular tissue, and the state of those stem cells. For example, stress, disease, and aging all diminish the capacity of adult stem cells to respond to injury, which in turn hinders tissue healing. One of the great unmet challenges for regenerative medicine is to devise ways to increase the numbers of these “endogenous” stem cells, and revive their ability to self-renew and proliferate.
  • The scientific basis for our work rests upon our demonstration that a naturally occurring stem cell growth factor, Wnt3a, can be packaged and delivered in such a way that it is robustly stimulates stem cells within an injured tissue to divide and self-renew. This, in turn, leads to unprecedented tissue healing in a wide array of bone injuries especially in aged animals. As California’s population ages, the cost to treat such skeletal injuries in the elderly will skyrocket. Thus, our work addresses a present and ongoing challenge to healthcare for the majority of Californians and the world, and we do it by mimicking the body’s natural response to injury and repair.
  • To our knowledge, there is no existing technology that displays such effectiveness, or that holds such potential for the stem cell-based treatment of skeletal injuries, as does a L-Wnt3a strategy. Because this approach directly activates the body’s own stem cells, it avoids many of the pitfalls associated with the introduction of foreign stem cells or virally reprogrammed autologous stem cells into the human body. In summary, our data show that L-Wnt3a constitutes a viable therapeutic approach for the treatment of skeletal injuries, especially those in individuals with diminished healing potential.
  • This progress report covers the period between Sep 01 2012through Aug 31 2013, and summarizes the work accomplished under ET funding TR1-01249. Under this award we developed a Wnt protein-based platform for activating a patient’s own stem cells for the purpose of tissue regeneration.
  • At the beginning of our grant period we generated research grade human WNT3A protein in quantities sufficient for all our discovery experiments. We then tested the ability of this WNT protein therapeutic to improve the healing response in animal models of stroke, heart attack, skin wounding, and bone fracture. These experimental models recapitulated some of the most prevalent and debilitating human diseases that collectively, affect millions of Californians.
  • At the end of year 2, we assembled an external review panel to select the promising clinical indication. The scientific advisory board unanimously selected skeletal repair as the leading indication. The WNT protein is notoriously difficult to purify; consequently in year 3 we developed new methods to streamline the purification of WNT proteins, and the packaging of the WNT protein into liposomal vesicles that stabilized the protein for in vivo use.
  • In years 3 and 4 we continued to accrue strong scientific evidence in both large and small animal models that a WNT protein therapeutic accelerates bone regeneration in critical size bony non-unions, in fractures, and in cases of implant osseointegration. In this last year of funding, we clarified and characterized the mechanism of action of the WNT protein, by showing that it activates endogenous stem cells, which in turn leads to faster healing of a range of different skeletal defects.
  • In this last year we also identified a therapeutic dose range for the WNT protein, and developed a route and method of delivery that was simultaneously effective and yet limited the body’s exposure to this potent stem cell factor. We initiated preliminary safety studies to identify potential risks, and compared the effects of WNT treatment with other commercially available bone growth factors. In sum, we succeeded in moving our early translational candidate from exploratory studies to validation, and are now ready to enter into the IND-enabling phase of therapeutic candidate development.
  • This progress report covers the period between Sep 01 2013 through April 30 2014, and summarizes the work accomplished under ET funding TR101249. Under this award we developed a Wnt protein-based platform for activating a patient’s own stem cells for purposes of tissue regeneration.
  • At the beginning of our grant period we generated research grade human WNT3A protein in quantities sufficient for all our discovery experiments. We then tested the ability of this WNT protein therapeutic to improve the healing response in animal models of stroke, heart attack, skin wounding, and bone fracture. These experimental models recapitulated some of the most prevalent and debilitating human diseases that collectively, affect millions of Californians. At the conclusion of Year 2 an external review panel was assembled and charged with the selection of a single lead indication for further development. The scientific advisory board unanimously selected skeletal repair as the lead indication.
  • In year 3 we accrued addition scientific evidence, using both large and small animal models, demonstrating that a WNT protein therapeutic accelerated bone healing. Also, we developed new methods to streamline the purification of WNT proteins, and improved our method of packaging of the WNT protein into liposomal vesicles (e.g., L-WNT3A) for in vivo use.
  • In year 4 we clarified the mechanism of action of L-WNT3A, by demonstrating that it activates endogenous stem cells and therefore leads to accelerated bone healing. We also continued our development studies, by identifying a therapeutic dose range for L-WNT3A, as well as a route and method of delivery that is both effective and safe. We initiated preliminary safety studies to identify potential risks, and compared the effects of L-WNT3A with other, commercially available bone growth factors.
  • In year 5 we initiated two new preclinical studies aimed at demonstrating the disease-modifying activity of L-WNT3A in spinal fusion and osteonecrosis. These two new indications were chosen by a CIRM review panel because they represent an unmet need in California and the nation. We also initiated development of a scalable manufacturing and formulation process for both the WNT3A protein and L-WNT3A formulation. These two milestones were emphasized by the CIRM review panel to represent major challenges to commercialization of L-WNT3A; consequently, accomplishment of these milestones is a critical yardstick by which progress towards an IND filing can be assessed.

Elucidating pathways from hereditary Alzheimer mutations to pathological tau phenotypes

Funding Type: 
Basic Biology V
Grant Number: 
RB5-07011
ICOC Funds Committed: 
$1 161 000
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Closed
Public Abstract: 
We propose to elucidate pathways of genes that lead from early causes to later defects in Alzheimer’s Disease (AD), which is common, fatal, and for which no effective disease-modifying drugs are available. Because no effective AD treatment is available or imminent, we propose to discover novel genetic pathways by screening purified human brain cells made from human reprogrammed stem cells (human IPS cells or hIPSC) from patients that have rare and aggressive hereditary forms of AD. We have already discovered that such human brain cells exhibit an unique biochemical behavior that indicates early development of AD in a dish. Thus, we hope to find new drug targets by using the new tools of human stem cells that were previously unavailable. We think that human brain cells in a dish will succeed where animal models and other types of cells have thus far failed.
Statement of Benefit to California: 
Alzheimer’s Disease (AD) is a fatal neurodegenerative disease that afflicts millions of Californians. The emotional and financial impact on families and on the state healthcare budget is enormous. This project seeks to find new drug targets to treat this terrible disease. If we are successful our work in the long-term may help diminish the social and familial cost of AD, and lead to establishment of new businesses in California using our approaches.

Misregulated Mitophagy in Parkinsonian Neurodegeneration

Funding Type: 
Basic Biology V
Grant Number: 
RB5-06935
ICOC Funds Committed: 
$1 174 943
Disease Focus: 
Parkinson's Disease
Neurological Disorders
Stem Cell Use: 
iPS Cell
oldStatus: 
Closed
Public Abstract: 
Parkinson’s disease (PD), is one of the leading causes of disabilities and death and afflicting millions of people worldwide. Effective treatments are desperately needed but the underlying molecular and cellular mechanisms of Parkinson’s destructive path are poorly understood. Mitochondria are cell’s power plants that provide almost all the energy a cell needs. When these cellular power plants are damaged by stressful factors present in aging neurons, they release toxins (reactive oxygen species) to the rest of the neuron that can cause neuronal cell death (neurodegeneration). Healthy cells have an elegant mitochondrial quality control system to clear dysfunctional mitochondria and prevent their resultant devastation. Based on my work that Parkinson’s associated proteins PINK1 and Parkin control mitochondrial transport that might be essential for damaged mitochondrial clearance, I hypothesize that in Parkinson’s mutant neurons mitochondrial quality control is impaired thereby leading to neurodegeneration. I will test this hypothesis in iPSC (inducible pluripotent stem cells) from Parkinson’s patients. This work will be a major step forward in understanding the cellular dysfunctions underlying Parkinson’s etiology, and promise hopes to battle against this overwhelming health danger to our aging population.
Statement of Benefit to California: 
Parkinson's disease (PD), one of the most common neurodegenerative diseases, afflicts millions of people worldwide with tremendous global economic and societal burdens. About 500,000 people are currently living with PD in the U.S, and approximate 1/10 of them live in California. The number continues to soar as our population continues to age. An effective treatment is desperately needed but the underlying molecular and cellular mechanisms of PD’s destructive path remain poorly understood. This proposal aims to explore an innovative and critical cellular mechanism that controls mitochondrial transport and clearance via mitophagy in PD pathogenesis with elegant employment of bold and creative approaches to live image mitochondria in iPSC (inducible pluripotent stem cells)-derived dopaminergic neurons from Parkinson’s patients. This study is closely relevant to public health of the state of California and will greatly benefit its citizens, as it will illuminate the pathological causes of PD and provide novel targets for therapuetic intervention.

Molecular Imaging for Stem Cell Science and Clinical Application

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

Stem Cell-Derived Astrocyte Precursor Transplants in Amyotrophic Lateral Sclerosis

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

Development of Novel Autophagy Inducers to Block the Progression of and Treat Amyotrophic Lateral Sclerosis (ALS) and Other Neurodegenerative Diseases

Funding Type: 
Early Translational IV
Grant Number: 
TR4-06693
ICOC Funds Committed: 
$2 278 080
Disease Focus: 
Amyotrophic Lateral Sclerosis
Neurological Disorders
Stem Cell Use: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
ALS is a progressive neurodegenerative disease that primarily affects motor neurons (MNs). It results in paralysis and loss of control of vital functions, such as breathing, leading to premature death. Life expectancy of ALS patients averages 2–5 years from diagnosis. About 5,600 people in the U.S. are diagnosed with ALS each year, and about 30,000 Americans have the disease. There is a clear unmet need for novel ALS therapeutics because no drug blocks the progression of ALS. This may be due to the fact that multiple proteins work together to cause the disease and therapies targeting individual toxic proteins will not prevent neurodegeneration due to other factors involved in the ALS disease process. We propose to develop a novel ALS therapy involving small molecule drugs that stimulate a natural defense system in MNs, autophagy, which will remove all of the disease-causing proteins in MNs to reduce neurodegeneration. We previously reported on a class of neuronal autophagy inducers (NAIs) and in this grant will prioritize those drugs for blocking neurodegeneration of human iPSC derived MNs from patients with familial and sporadic ALS to identify leads that will then be tested for efficacy in vivo in animal models of ALS to select a clinical candidate. Since all of our NAIs are FDA approved for treating indications other than ALS, our clinical candidate could be rapidly transitioned to testing for efficacy and safety in treating ALS patients near the end of this grant.
Statement of Benefit to California: 
Neurodegenerative diseases such as ALS as well as Alzheimer’s (AD), Parkinson’s (PD) and Huntington’s Disease (HD) are devastating to the patient and family and create a major financial burden to California (CA). These diseases are due to the buildup of toxic misfolded proteins in key neuronal populations that leads to neurodegeneration. This suggests that common mechanisms may be operating in these diseases. The drugs we are developing to treat ALS target this common mechanism, which we believe is an impairment of autophagy that prevents clearance of disease-causing proteins. Effective autophagy inducers we identify to treat ALS may turn out to be effective in treating other neurodegenerative diseases. This could have a major impact on the health care in CA. Most important in our studies is the translational impact of the use of patient iPSC-derived neurons and astrocytes to identify a new class of therapeutics to block neurodegeneration that can be quickly transitioned to testing in clinical trials for treating ALS and other CNS diseases. Future benefits to CA citizens include: 1) development of new treatments for ALS with application to other diseases such as AD, HD and PD that affect thousands of individuals in CA; 2) transfer of new technologies to the public realm with resulting IP revenues coming into the state with possible creation of new biotechnology spin-off companies and resulting job creation; and 3) reductions in extensive care-giving and medical costs.

A drug-screening platform for autism spectrum disorders using human astrocytes

Funding Type: 
Early Translational IV
Grant Number: 
TR4-06747
ICOC Funds Committed: 
$1 824 719
Disease Focus: 
Autism
Neurological Disorders
Rett's Syndrome
Pediatrics
Stem Cell Use: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
Autism spectrum disorders (ASD) are complex neurodevelopmental diseases that affect about 1% of children in the United States. Such diseases are mainly characterized by deficits in verbal communication, impaired social interaction, and limited and repetitive interests and behavior. The causes and best treatments remain uncertain. One of the major impediments to ASD research is the lack of relevant human disease models. Reprogramming of somatic cells to a pluripotent state (induced pluripotent stem cells, iPSCs) has been accomplished using human cells. Isogenic pluripotent cells are attractive from the prospective to understanding complex diseases, such as ASD. The main goal of this project is to accelerate drug discovery to treat ASD using astrocytes generated from human iPSC. The model recapitulates early stages of ASD and represents a promising cellular tool for drug screening, diagnosis and personalized treatment. By testing whether drugs have differential effects in iPSC-derived astrocytes, we can begin to unravel how genetic variation in ASD dictates responses to different drugs. Insights that emerge from our studies may drive the development of new therapeutic interventions for ASD. They may also illuminate possible differences in drug responsiveness in different patients and potentially define a molecular signature resulting from ASD variants, which could predict the onset of disease before symptoms are seen.
Statement of Benefit to California: 
Autism spectrum disorders, including Rett syndrome, Angelman syndrome, Timothy syndrome, Fragile X syndrome, Tuberous sclerosis, Asperger syndrome or childhood disintegrative disorder, affect many Californian children. In the absence of a functionally effective cure or early diagnostic tool, the cost of caring for patients with such pediatric diseases is high, in addition to a major personal and family impact since childhood. The strikingly high prevalence of ASD, dramatically increasing over the past years, has led to the emotional view that ASD can be traced to a single source, such as vaccine, preservatives or other environmental factors. Such perspective has a negative impact on science and society in general. Our major goal is to develop a drug-screening platform to rescue deficiencies showed from brain cells derived from induced pluripotent stem cells generated from patients with ASD. If successful, our model will bring novel insights on the dentification of potential diagnostics for early detection of ASD risk, or ability to predict severity of particular symptoms. In addition, the development of this type of pharmacological therapeutic approach in California will serve as an important proof of principle and stimulate the formation of businesses that seek to develop these types of therapies (providing banks of inducible pluripotent stem cells) in California with consequent economic benefit.

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