Neurological Disorders

Coding Dimension ID: 
303
Coding Dimension path name: 
Neurological Disorders
Funding Type: 
Preclinical Development Awards
Grant Number: 
PC1-08117
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$4 951 623
Disease Focus: 
Huntington's Disease
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 

Huntington’s disease (HD) is a devastating degenerative brain disease with at least a 1 in 10,000 prevalence that inevitably leads to death. These numbers do not fully reflect the large societal and familial cost of HD, which requires extensive care-giving. HD has no effective treatment or cure and symptoms unstoppably progress for 15-20 years, with onset typically striking in midlife. Because HD is genetically dominant, the disease has a 50% chance of being inherited by the children of patients. Symptoms of the disease include uncontrolled movements, difficulties in carrying out daily tasks or continuing employment, and severe psychiatric manifestations including depression. Current treatments only address some symptoms and do not change the course of the disease, therefore a completely unmet medical need exists. Human embryonic stem cells (hESCs) and their derivatives offer a possible long-term treatment approach that could relieve the tremendous suffering experienced by patients and their families. HD is the 3rd most prevalent neurodegenerative disease, but because it is entirely genetic and the mutation known, a diagnosis can be made with certainty and clinical applications of hESCs may provide insights into treating brain diseases that are not caused by a single, known mutation. Trials in mice where protective factors were directly delivered to the brains of HD mice have been effective, suggesting that delivery of these factors by hESCs may help patients. Transplantation of tissue in HD patients suggests that replacing neurons that are lost may also be effective. The ability to differentiate hESCs into neural populations offers a powerful and sustainable alternative to provide neuroprotection to the brain with the possibility of cell replacement. We have assembled a multidisciplinary team of investigators and consultants with expertise in basic, translational and clinical development and have identified a lead developmental candidate, ESI-017 neural stem cells, that have disease modifying activity in HD mice with sufficient promise to perform systematic efficacy and safety studies in HD mice with cells generated for this project. We will utilize the collaborative research team, additional preclinical and clinical investigators, stem cell experts and FDA consultants to finalize work that will lead to a productive pre-IND meeting with the FDA and a path forward for clinical trials with the neural stem cell development candidate.

Statement of Benefit to California: 

The disability and loss of earning power and personal freedom resulting from Huntington's disease (HD) is devastating and creates a financial burden for California. Individuals are struck in the prime of life, at a point when they are their most productive and have their highest earning potential. As the disease progresses, individuals require institutional care at great financial cost. Therapies using human embryonic stem cells (hESCs) have the potential to change the lives of hundreds of individuals and their families, which brings the human cost into the thousands. For the potential of hESCs in HD to be realized, we have brought together a team of investigators highly experienced in HD basic science and preclinical development, stem cell research, HD clinical trials and FDA regulatory activities to evaluate a human stem cell derived neural stem cell line, ESI-107 NSC in HD mouse models. This selection of this development candidate is based on efficacy in behavioral and electrophysiology measurements in a rapidly progressing mouse model of HD. HD is the 3rd most prevalent neurodegenerative disease, but because it is entirely genetic and the mutation known, a diagnosis can be made with certainty and clinical applications of NSCs may provide insights into treating brain diseases that are not caused by a single, known mutation. We have assembled a strong team of California-based investigators to carry out proposed studies to move ESI-017 NSCs to the point of a productive pre-IND meeting with the FDA to ultimately move this clinical product into Investigative New Drug-enabling (IND) activities with the goal of performing clinical trials in HD subjects. Anticipated benefits to the citizens of California include: 1) development of new human stem cell-based treatments for HD with application to other neurodegenerative diseases such as Alzheimer's and Parkinson's diseases that affect thousands of individuals in California; 2) improved methods for following the course of the disease in order to treat HD as early as possible before symptoms are manifest; 3) transfer of new technologies and intellectual property to the public realm with resulting IP revenues coming into the state with possible creation of new biotechnology spin-off companies; and 4) reductions in extensive care-giving and medical costs. It is anticipated that the return to the State in terms of revenue, health benefits for its Citizens and job creation will be substantial.

Funding Type: 
Alpha Stem Cell Clinics
Grant Number: 
AC1-07764
Investigator: 
ICOC Funds Committed: 
$8 000 000
Disease Focus: 
Diabetes
Spinal Cord Injury
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
Adult Stem Cell
Cell Line Generation: 
Embryonic Stem Cell
Adult Stem Cell
Public Abstract: 

The proposed alpha clinic will bring together an outstanding team of physician-scientists with substantial clinical trials experience including stem cell and other cellular treatments of blood diseases and others. This team will also draw on our unique regional competitive advantages derived from our history of extensive collaboration with investigators at many nearby first-class research institutions and biotech companies. We propose to include these regional assets in our plans to translate our successful research on basic properties of stem cells to stem cell clinical trials and ultimately to delivery of effective and novel therapies. We propose to build an alpha clinic that serves the stem cell clinical trial needs of our large region where we are the only major academic health center with the needed expertise to establish a high impact alpha clinic. Our infrastructure will initially be developed and then used to support two major high-impact stem cell clinical trials: one in type I diabetes and one in spinal cord injury. Both are collaborations with established and well known companies. The type I diabetes trial will test embryonic stem cell derived cells that differentiate to become the missing beta cells of the pancreas. The cells are contained in a semipermeable bag that has inherent safety because of restriction of cell migration while allowing proper control of insulin levels in response to blood sugar. These hybrid devices are implanted just beneath the skin in patients in these trials. In a second trial of stem cell therapy for spinal cord injury, neuronal stem cells that have been shown to have substantial safety and efficacy in animal models of spinal cord injury and other types of spinal cord trauma or disease will be tested in human patients with chronic spinal cord injury. Both of these trials have the potential to have very substantial and important impact on patients with these diseases and the families and society that supports them. Following on these two trials, we are planning stem cell clinical trials for heart failure, cancer, ALS, and other terrible deadly disorders. Our proposed alpha clinic also benefits from very substantial leveraged institutional commitments, which will allow for an alpha clinic that is sustainable well beyond the five-year grant, which is essential to continue to manage the patients who have participated in the first trials being planned since multi-year followup and tracking is essential scientifically and ethically. We have a plan for our proposed alpha clinic to be sustainable to 10 years and beyond to the point at which these therapies if successful will be delivered to patients in our healthcare system.

Statement of Benefit to California: 

Many terrible diseases that afflict the citizens of California and cause substantial economic and emotional disruption to California families can potentially be treated with novel stem cell therapies. These therapies need to be tested in a rigorous and unbiased fashion in clinical trials, which is the focus of our proposed alpha clinic. Our clinic proposes to begin with clinical trials in two major diseases in need of improved treatment: type I diabetes and spinal cord injuries. The type I diabetes clinical trial will test a novel hybrid embryonic stem cell-derived pancreatic cell/encapsulation technology that is implanted just beneath the skin in an out-patient procedure, and is inherently safe because the cells are confined to a semi-permeable bag. The spinal cord injury trial will test the benefit of neural stem cells delivered to the site of injury. Both have substantial positive evidence in animal models and have the potential of leading to major breakthroughs. In addition to providing the infrastructure for these two trials, our proposed alpha clinic will also take advantage of very substantial regional expertise at our partner institutions to test stem cells in other diseases of importance in California including heart failure, ALS, cancer, and many others. Our proposed alpha clinic will also be a major economic as well as medical driver as it leverages substantial institutional and private sector commitment, and has the potential to deliver breakthrough therapies that will be marketed either in a health care system or by private sector companies.

Funding Type: 
Disease Team Therapy Development - Research
Grant Number: 
DR2A-05415
Investigator: 
Type: 
PI
Name: 
Type: 
Co-PI
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
  • Background: Huntington’s disease (HD) is a genetically inherited, fatal neuropsychiatric disorder which strikes 1/10,000 people. The cause is a repeat expansion in the Huntingtin gene which leads to progressive brain degeneration, ultimately resulting in death after 15-20 years. HD passes from generation to generation. Each child of a parent with HD has a 50% chance of inheriting the HD mutation. There is currently no treatment, therapy or medication that will delay the onset of the disease or slow its progression. All currently available treatments are palliative, which focus on symptom management alone. There is currently no cure for HD.
  • Proposed therapy: We propose a novel therapy for HD: implantation of mesenchymal stem cells engineered to secrete Brain-Derived Neurotrophic Factor (MSC/BDNF). BDNF levels are reduced in the brains of HD patients. BDNF has been shown in numerous transgenic HD mouse studies to prevent cell death and to stimulate the growth and migration of new neurons in the brain, and is thus a lead candidate for neuroprotection in HD. We are using MSCs as delivery vehicles to produce BDNF in the affected areas of the striatum. We are conducting detailed tests of MSC/BDNF in HD mouse models 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.
  • Progress, Year 2 of grant: Based on recommendations from the CIRM Clinical Development Advisory Panel (CDAP), we altered our vector and added a second animal model. Following CDAP, we repeated all manufacturing and testing of MSC/BDNF using the new vector, produced using Standard Operating Procedures (SOPs) from our UC Davis Good Manufacturing Practices (GMP) Facility. We have shown that MSC/BDNF produces high levels of BDNF and that a multiplicity of infection of ten virus particles per cell generates a single unrearranged integrant per cell, on average. This is data critical to the Recombinant DNA Advisory Committee (RAC), for whom we have prepared an Appendix M application. RAC approval is needed prior to FDA approval because it is a proposed stem cell gene therapy trial. We are currently refining our application to the FDA and will seek CIRM approval for submission.
  • We are completing our double-blinded studies, now using the new vector, examining the effects on disease progression of implantation of MSC/BDNF in two strains of HD transgenic mice: YAC 128 and R6/2 (CAG 120). The R6/2 (CAG 120) model has the early onset of neurologic dysfunction and dies much earlier than wild-type of YAC 128 models. For this reason it is a more suitable model of juvenile HD. In the R6/2 model we have successfully demonstrated that implantation of MSC/BDNF causes an improvement in deficits in open field exploration, a behavioral assay. We have also shown that MSC/BDNF causes increased neurogenesis in the brain of treated mice, an important milestone.
  • The YAC 128 model develops slowly progressive behavior symptoms in mid-life and has loss of brain cells that mirrors changes seen in HD patients. In the YAC 128 model we have shown that implantation of our MSC/BDNF product decreases striatal atrophy between 8 and 12 months of age. Wild type mice have a typical lifespan of two years, so this age in the YAC 128 mouse roughly corresponds to the typical age at onset for early-stage HD patients that we are proposing to treat in our future planned Phase 1 study, HD-CELL.
  • Clinical Update: In tandem with the on-going preIND studies in the lab, the clinical team is conducting an observational study, PRE-CELL. The goal of PRE-CELL is to establish baseline characteristics and track disease progression in a group of early stage HD patients. PRE-CELL subjects undergo detailed neurological, psychiatric, cognitive, imaging and laboratory testing, including measurement of BDNF levels. PRE-CELL participants who have completed at least 1 year of follow-up and meet inclusion and exclusion criteria will be considered for the future planned cell therapy trial. PRE-CELL has been approved by the Institutional Review Board at UC Davis since July 2013 and is still enrolling. For additional information, please go to: ClinicalTrials.gov Identifier: NCT01937923.
  • Significance: Our progress to date supports the completion of our final pre-clinical studies and our plan to go forward toward regulatory approval. There are potential applications of our research beyond HD. 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. It also provides a platform for our future gene editing studies, since we will again use MSCs to deliver the needed molecules into the neurons.
Funding Type: 
Tools and Technologies II
Grant Number: 
RT2-01965
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$1 327 983
Disease Focus: 
Parkinson's Disease
Neurological Disorders
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 

The goal of this proposal is to establish a novel research tool to explore the molecular basis of Parkinson’s disease (PD) - a critical step toward the development of new therapy. To date, a small handful of specific genes and associated mutations have been causally linked to the development of PD. However, how these mutations provoke the degeneration of specific neurons in the brain remains poorly understood. Moreover, conducting such genotype-phenotype studies has been hampered by two significant experimental problems. First, we have historically lacked the ability to model the relevant human cell types carrying the appropriate gene mutation. Second, the genetic variation between individuals means that the comparison of a cell from a disease-carrier to a cell derived from a normal subject is confounded by the many thousands of genetic changes that normally differentiate two individuals from one another. Here we propose to combine two powerful techniques – one genetic and one cellular – to overcome these barriers and drive a detailed understanding of the molecular basis of PD. Specifically, we propose to use zinc finger nucleases (ZFNs) in patient-derived induced pluripotent stem cells (iPSC) to accelerate the generation of a panel of genetically identical cell lines differing only in the presence or absence of a single disease-linked gene mutation. iPSCs have the potential to differentiate into many cell types – including dopaminergic neurons that become defective in PD. Merging these two technologies will thus allow us to study activity of either the wild-type or the mutant gene product in cells derived from the same individual, which is critical for elucidating the function of these disease-related genes and mutations. We anticipate that the generation of these isogenic cells will accelerate our understanding of the molecular causes of PD, and that such cellular models could become important tools for developing novel therapies.

Statement of Benefit to California: 

Approx. 36,000-60,000 people in the State of California are affected with Parkinson’s disease (PD) – a number that is estimated to double by the year 2030. This debilitating neurodegenerative disease causes a high degree of disability and financial burden for our health care system.

Importantly, recent work has identified specific gene mutations that are directly linked to the development of PD. Here we propose to exploit the plasticity of human induced pluripotent stem cells (iPSC) to establish models of diseased and normal tissues relevant to PD. Specifically, we propose to take advantage of recent developments allowing the derivation of stem cells from PD patients carrying specific mutations. Our goal is to establish advanced stem cell models of the disease by literally “correcting” the mutated form of the gene in patient cells, therefore allowing for direct comparison of the mutant cells with its genetically “repaired” yet otherwise identical counterpart. These stem cells will be differentiated into dopaminergic neurons, the cells that degenerate in the brain of PD patients, permitting us to study the effect of correcting the genetic defect in the disease relevant cell type as well as provide a basis for the establishment of curative stem cells therapies.

This collaborative project provides substantial benefit to the state of California and its citizens by pioneering a new stem cell based approach for understanding the role of disease causing mutations via “gene repair” technology, which could ultimately lead to advanced stem cell therapies for Parkinson’s disease – an unmet medical need without cure or adequate long-term therapy.

Progress Report: 
  • The goal of this proposal was to establish a novel research tool to explore the molecular basis of Parkinson’s disease (PD) - a critical step toward the development of new therapy. To date, a small handful of specific genes and associated mutations have been causally linked to the development of PD. However, how these mutations provoke the degeneration of specific neurons in the brain remains poorly understood.
  • In the first year of the grant, we have successfully modified the LRRK2 G2019S mutation in patient-derived induced pluripotent stem cells (iPSC) using zinc-finger technology. We created several clonal lines with the gene correction and also with a knockdown of the LRRK2 gene.
  • We characterized these lines for pluripotency, karyotype, and differentiation potential and currently, we are testing the lines for functional differences in the next reporting period and will generate iPSCs with specific LRRK2 mutations introduced using zinc-finger technology.
  • Despite the growing number of diseases linked to single gene mutations, determining the molecular mechanisms by which such errors result in disease pathology has proven surprisingly difficult. The ability to correlate disease phenotypes with a specific mutation can be confounded by background of genetic and epigenomic differences between patient and control cells. To address this problem, we employed zinc finger nucleases-based genome editing in combination with a newly developed high-efficiency editing protocol to generate isogenic patient-derived induced pluripotent stem cells (iPSC) differing only at the most common mutation for Parkinson's disease (PD), LRRK2 p.G2019S. We show that correction of the LRRK2 p.G2019S mutation rescues a panel of neuronal cell phenotypes including reduced dopaminergic cell number, impaired neurite outgrowth and mitochondrial dysfunction. These data reveal that PD-relevant cellular pathophysiology can be reversed by genetic repair, thus confirming the causative role of this prevalent mutation – a result with potential translational implications.
  • The goal of this proposal has been to establish a novel research tool to explore the molecular basis of Parkinson’s disease (PD) - a critical step toward the development of new therapies. To date, a small handful of specific genes and associated mutations have been causally linked to the development of PD. However, how these mutations provoke the degeneration of specific neurons in the brain remains poorly understood.
  • Moreover, conducting such genotype-phenotype studies has been hampered by two significant experimental problems. First, we have historically lacked the ability to model the relevant human cell types carrying the appropriate gene mutation. Second, the genetic variation between individuals means that the comparison of a cell from a disease-carrier to a cell derived from a normal subject is confounded by the many thousands of genetic changes that normally differentiate two individuals from one another.
  • We proposed to use zinc finger nucleases (ZFNs) in patient-derived induced pluripotent stem cells (iPSC) to accelerate the generation of a panel of genetically identical cell lines differing only in the presence or absence of a single disease-linked gene mutation.
  • To this end, we have successfully generated a panel of LRRK2 isogenic cell lines that differ only in "one building block" in the genomic DNA of a cell which can cause PD, therefore we genetically 'cured' the cells in the culture dish. These lines are invaluable because they are a set of tools that allow to study the effect of this mutation in the context of neurodegeneration and cell death. We received interest from many outside academic laboratories and industry to distribute these novel tools and these cell lines will hopefully lead to the discovery of new drugs that can halt or even reverse PD.
  • Being afflicted with a chronic, progressive disease means that it never stops, it is there in the morning when you wake up and it is the last thing at night that you feel when you are falling asleep. Parkinson’s disease (PD) makes you slowly lose body functions that you once took for granted. Eating tasks become more challenging as well as chewing and swallowing, simple motor movements such as turning in bed or getting out of the car or a deep chair takes a lot of extra effort. You might also show signs of depression, anxiety, even hallucinations or just feeling indifferent towards hobbies/activities or being with loved ones. Autonomic functions are affected with lightheadedness, constipation, or urine control. You might lose your sense of smell, have changes in heart rate, and sleep problems. All these changes can occur at once or become apparent over time. Not everyone with PD is experiencing all of these symptoms. Every disease is different and the symptoms can be diverse. PD is a “designer disease” and needs a targeted approach clinically and scientifically.
  • In this CIRM project, we focused on the clinical and genetic variability and used gene editing technology to modify the genome at precise positions (“correct genetic mutations”) known to cause clinically and neuropathologically PD. The newly created patient-derived pluripotent stem cell lines only differ at the known positions and “off-target” modifications were excluded and we were able to experimentally show that the change in the genetic sequence is “rescuing” the cellular changes relevant for PD.
  • The advantage of these patient-specific cell lines are that specific genetic changes can be directly investigated without the experimental noise in control cell lines. This approach has been adopted by many laboratories in the field of disease modeling and will probably become the gold standard for stem cell modeling and drug discovery.
Funding Type: 
Strategic Partnership III Track A
Grant Number: 
SP3A-07552
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$14 323 318
Disease Focus: 
Spinal Cord Injury
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 

The proposed project is designed to assess the safety and preliminary activity of escalating doses of human embryonic stem cell derived oligodendrocyte progenitor cells (OPCs) for the treatment of spinal cord injury. OPCs have two important functions: they produce factors which stimulate the survival and growth of nerve cells after injury, and they mature in the spinal cord to produce myelin, the insulation which enables electrical signals to be conducted within the spinal cord.

Clinical testing of this product initiated in 2010 after extensive safety and efficacy testing in more than 20 nonclinical studies. Initial clinical safety testing was conducted in five subjects with neurologically complete thoracic injuries. No safety concerns have been observed after following these five subjects for more than two years. The current project proposes to extend testing to subjects with neurologically complete cervical injuries, the intended population for further clinical development, and the population considered most likely to benefit from the therapy. Initial safety testing will be performed in three subjects at a low dose level, with subsequent groups of five subjects at higher doses bracketing the range believed most likely to result in functional improvements. Subjects will be monitored both for evidence of safety issues and for signs of neurological improvement using a variety of neurological, imaging and laboratory assessments.

By completion of the project, we expect to have accumulated sufficient safety and dosing data to support initiation of an expanded efficacy study of a single selected dose in the intended clinical target population.

Statement of Benefit to California: 

The proposed project has the potential to benefit the state of California by improving medical outcomes for California residents with spinal cord injuries (SCIs), building on California’s leadership position in the field of stem cell research, and creating high quality biotechnology jobs for Californians.

Over 12,000 Americans suffer an SCI each year, and approximately 1.3 million people in the United States are estimated to be living with a spinal cord injury. Although specific estimates for the state of California are not available, the majority of SCI result from motor vehicle accidents, falls, acts of violence, and recreational sporting activities, all of which are common in California. Thus, the annual incidence of SCI in California is likely equal to or higher than the 1,400 cases predicted by a purely population-based distribution of the nationwide incidence.

The medical, societal and economic burden of SCI is extraordinarily high. Traumatic SCI most commonly impacts individuals in their 20s and 30s, resulting in a high-level of permanent disability in young and previously healthy individuals. At one year post injury, only 11.8% of SCI patients are employed, and fewer than 35% are employed even at more than twenty years post-injury (NSCISC Spinal Cord Injury Facts and Figures 2013). Life expectancies of SCI patients are significantly below those of similar aged patients with no SCI. Additionally, many patients require help with activities of daily living such as feeding and bathing. As a result, the lifetime cost of care for SCI patients are enormous; a recent paper (Cao et al 2009) estimated lifetime costs of care for a patient obtaining a cervical SCI (the population to be enrolled in this study) at age 25 at $4.2 million. Even partial correction of any of the debilitating consequences of SCI could enhance activities of daily living, increase employment, and decrease reliance on attendant and medical care, resulting in substantial improvements in both quality of life and cost of care for SCI patients.

California has a history of leadership both in biotechnology and in stem cell research. The product described in this application was invented in California, and has already undergone safety testing in five patients in a clinical study initiated by a California corporation. The applicant, who has licensed this product from its original developer and recruited many of the employees responsible for its previous development, currently employs 17 full-time employees at its California headquarters, with plans to significantly increase in size over the coming years. The successful performance of the proposed project would enable significant additional jobs creation in preparation for pivotal trials and product registration.

Funding Type: 
Tools and Technologies III
Grant Number: 
RT3-07616
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$1 308 711
Disease Focus: 
Amyotrophic Lateral Sclerosis
Neurological Disorders
Spinal Cord Injury
Spinal Muscular Atrophy
Stem Cell Use: 
Embryonic Stem Cell
Cell Line Generation: 
Embryonic Stem Cell
Public Abstract: 

Motor neurons degenerate and die as a consequence of many conditions, including trauma to the spinal cord and its nerve roots and degenerative diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy. Paralysis and in many cases death may result from a loss of motor neurons. No effective treatments are available for these patients. Most cellular therapy studies for motor neuron disorders are done in rodents. However, because of the dramatic differences between the rodent and human spinal cord, translation of these studies to humans is difficult. In particular, the development of new stem cell based treatments is limited by the lack of large animal models to test promising candidate therapies.
This bottleneck will be addressed by developing a new research tool in which human embryonic stem cell-derived motor neurons are transplanted into the spinal cord of rhesus macaques after injury and surgical repair of motor nerve roots. This injury and repair model mimic many features of motor neuron degeneration in humans. Microscopic studies will determine survival and tissue integration of transplanted human cells in the primate spinal cord tissues. Evaluations of walking, muscle and bladder function, sensation and magnetic resonance imaging (MRI) will test for possible benefits and potential adverse effects. This new research tool will be available for future pre-clinical testing of additional stem cell-based therapies that target motor neuron loss.

Statement of Benefit to California: 

Paralysis resulting from motor neuron loss after cauda equina and conus medullaris forms of spinal cord injury and from neurodegenerative conditions, such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are devastating and affects thousands of patients and their families in California (CA). These conditions also create a significant financial burden on the state of CA. No effective treatments are available for these underserved patients. Development of a clinically relevant research tool is proposed to evaluate emerging stem cell-based motor neuron replacement therapies in translational studies. No such models are presently available to the global research community. As a result, the proposed research tool, which will remain based in CA, may attract interest across the United States and abroad, potentially being able to tap into a global translational research market of stem cell-based therapies and contribute to a positive revenue flow to CA.
Future benefits to people in CA include: 1) Development and translation of a new CA-based research tool to facilitate and expedite clinical realization of emerging stem cell-based therapies for devastating neurological conditions affecting motor neurons; 2) Reduction of health care costs and care giver costs for chronic motor neuron conditions with paralysis; 3) Potential for revenue from intellectual properties related to new cellular treatments entering clinical trials and human use.

Funding Type: 
Basic Biology V
Grant Number: 
RB5-07363
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$1 178 370
Disease Focus: 
Stroke
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

Stem cell therapy holds promise for the almost million Americans yearly who suffer a stroke. Preclinical data have shown that human neural stem cells (hNSCs) aid recovery after stroke, resulting in a major effort to advance stem cell therapy to the clinic, and we are currently transitioning our hNSC product to the clinic for stroke therapy. In this proposal we will explore how these cells improve lost function. We have already shown that injected hNSCs secrete factors that promote the gross rewiring of the brain, a major component of the spontaneous recovery observed after stroke. We now intend to focus on the connections between neurons, the synapses, which are a critical part of this rewiring process. We aim to quantify the effect of hNSCs on synapse density and function, and explore whether the stem cells secrete restorative synaptogenic factors or form functional synapses with pre-existing neurons. Our pursuit is made possible by our combination of state-of-the-art imaging techniques enabling us to visualize, characterize, and quantify these tiny synaptic structures and their interaction with the hNSCs. Furthermore, by engineering the hNSCs we can identify the factors they secrete in the brain and identify those which modulate synaptic connections. Our proposed studies will provide important insight into how transplanted stem cells induce recovery after stroke, with potential applicability to other brain diseases.

Statement of Benefit to California: 

Cerebrovascular stroke is the fourth leading cause of mortality in the United States and a significant source of long-term physical and cognitive disability that has devastating consequences to patients and their families. In California alone, over 9% of adults 65 years or older have had a stroke according to a 2005 study. In the next 20 years the societal toll is projected to amount to millions of patients and 18.8 billion dollars per year in direct medical costs. To date, there is no approved therapeutic agent for the recovery phase after stroke, making the long-term care of stroke patients a tremendous socioeconomic burden that will continue to rise as our aging population increases. Our laboratory and others have demonstrated the promise of stem cell transplantation to treat stroke. We are dedicated to developing human neural stem cells (hNSCs) as a novel neuro-restorative treatment for lost motor function after stroke. The goal of our proposed work is to further understand how transplanted hNSCs improve stroke recovery, as dissecting the mechanism of action of stem cells in the stroke brain will ultimately improve the chance of clinical success. This could potentially provide significant cost savings to California, but more importantly benefit the thousands of Californians and their families who struggle with the aftermath of stroke.

Progress Report: 
  • Stroke is a leading cause of disability in the United States, yet it has limited treatment options. Stem cell therapy offers a novel therapeutic strategy for stroke, and several clinical trials are underway. We are investigating the mechanisms by which stem cells enhance recovery in preclinical animal models of stroke. In the first year of this award we have found that after transplanting our stem cells into the stroke brain they only survive for a short time, and die before their effect on behavior recovery is observable. This implies that the transplanted cells act by triggering a cascade of events while they are present, which eventually leads to recovery. We are investigating what these ‘trigger’ events are. To this end we have made significant progress in developing sensitive tests to measure the effects of the transplanted cells on brain activity, plasticity, and inflammation. We are making on-track progress investigating how the stem cell-induced changes in these parameters relate to cell-induced functional recovery.
Funding Type: 
Basic Biology V
Grant Number: 
RB5-06935
Investigator: 
Institution: 
Type: 
PI
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.

Progress Report: 
  • Mitochondria are a 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. It is not surprising that the impairment in this mitochondrial quality control system has been linked to Parkinson’s disease (PD), one of the most common neurodegenerative diseases. Based on my work that Parkinson’s associated proteins PINK1 and Parkin halt mitochondrial transport that might be essential for the damaged mitochondrial clearance, I hypothesized that in Parkinson’s mutant neurons mitochondrial quality control is impaired thereby leading to neurodegeneration, in the original application. For the past year, we have made substantial progress in achieving the specific aims. Briefly, we found that the pathogenic G2019S mutation in LRRK2 increases mitochondrial movement and disrupts mitochondrial quality control. These functional deficits are present in multiple independent disease models, including induced pluripotent stem cell (iPSC)-derived neurons and skin fibroblasts from familial PD patients. Mutations in LRRK2 are the most frequent cause of PD. Intriguingly, we also identified the same mitochondrial impairments in sporadic PD patients. Thus, disrupted mitochondrial quality control may constitute a central component of PD pathogenesis. Remarkably, arresting mitochondrial motility by genetic manipulations in LRRK2G2019S iPSC-derived neurons restores mitochondrial quality control and rescues neurodegeneration. We therefore propose that therapeutic targeting of mitochondrial quality control may be broadly effective for multiple forms of PD, including sporadic cases.
Funding Type: 
Tools and Technologies II
Grant Number: 
RT2-01975
Investigator: 
ICOC Funds Committed: 
$1 831 723
Disease Focus: 
Neurological Disorders
Parkinson's Disease
oldStatus: 
Active
Public Abstract: 

The surgical tools currently available to transplant cells to the human brain are crude and underdeveloped. In current clinical trials, a syringe and needle device has been used to inject living cells into the brain. Because cells do not spread through the brain tissue after implantation, multiple brain penetrations (more than ten separate needle insertions in some patients) have been required to distribute cells in the diseased brain region. Every separate brain penetration carries a significant risk of bleeding and brain injury. Furthermore, this approach does not result in effective distribution of cells. Thus, our lack of appropriate surgical tools and techniques for clinical cell transplantation represents a significant roadblock to the treatment of brain diseases with stem cell based therapies. A more ideal device would be one that can distribute cells to large brain areas through a single initial brain penetration.

In rodents, cell transplantation has successfully treated a great number of different brain disorders such as Parkinson’s disease, epilepsy, traumatic brain injury, multiple sclerosis, and stroke. However, the human brain is about 500 times larger than the mouse brain. While the syringe and needle transplantation technique works well in mice and rats, using this approach may not succeed in the much larger human brain, and this may result in failure of clinical trials for technical reasons.

We believe that the poor design of current surgical tools used for cell delivery is from inadequate interactions between basic stem cell scientists, medical device engineers, and neurosurgeons. Using a multidisciplinary approach, we will first use standard engineering principles to design, fabricate, refine, and validate an innovative cell delivery device that can transplant cells to a large region of the human brain through a single brain penetration. We will then test this new prototype in a large animal brain to ensure that the device is safe and effective. Furthermore, we will create a document containing engineering drawings, manufacturing instructions, surgical details, and preclinical data to ensure that this device is readily available for inclusion in future clinical trials.

By improving the safety and efficacy of cell delivery to the brain, the development of a superior device for cell transplantation may be a crucial step on the road to stem cell therapies for a wide range of brain diseases. In addition, devices and surgical techniques developed here may also be advantageous for use in other diseased organs.

Statement of Benefit to California: 

The citizens of California have invested generously into stem cell research for the treatment of human diseases. While significant progress has been made in our ability to produce appropriate cell types in clinically relevant numbers for transplantation to the brain, these efforts to cure disease may fail because of our inability to effectively deliver the cells. Our proposed development of a superior device for cell transplantation may thus be a crucial step on the road to stem cell therapies for a wide range of brain disorders, such as Parkinson’s disease, stroke, brain tumors, epilepsy, multiple sclerosis, and traumatic brain injury. Furthermore, devices and surgical techniques developed in our work may also be advantageous for use in other diseased organs. Thus, with successful completion of our proposal, the broad community of stem cell researchers and physician-scientists will gain access to superior surgical tools with which to better leverage our investment into stem cell therapy.

Progress Report: 
  • The surgical tools currently available to transplant cells to the human brain are crude and underdeveloped. In current clinical trials, a syringe and needle device has been used to inject living cells into the brain. Because cells do not spread through the brain tissue after implantation, multiple brain penetrations (more than ten separate needle insertions in some patients) have been required to distribute cells in the diseased brain region. Every separate brain penetration carries a significant risk of bleeding and brain injury. Furthermore, this approach does not result in effective distribution of cells. Thus, our lack of appropriate surgical tools and techniques for clinical cell transplantation represents a significant roadblock to the treatment of brain diseases with stem cell based therapies. A more ideal device would be one that can distribute cells to large brain areas through a single initial brain penetration.
  • In this first year of progress, we have designed, prototyped, and tested a stereotactic neurosurgical device capable of delivering cells to a volumetrically large target region through a single cortical brain penetration. We compared the performance of our device to a currently used cell transplantation implement – a 20G cannula with dual side ports. Through a single initial penetration, our device could transplant materials to a region greater than 4 cubic centimeters. Modeling with neurosurgical planning software indicated that our device could distribute cells within the entire human putamen – a target used in Parkinson’s disease trials – via a single transcortical penetration. While reflux of material along the penetration tract was problematic with the 20G cannula, resulting in nearly 80% loss of cell delivery, our device was resistant to reflux. We also innovated an additional system that facilitates small and precise volumes of injection. Both dilute and highly concentrated neural precursor cell populations tolerated transit through the device with high viability and unaffected developmental potential. Our device design is compatible with currently employed frame-based, frameless, and intraoperative MRI stereotactic neurosurgical targeting systems.
  • The surgical tools currently available to transplant cells to the human brain are crude and underdeveloped. In current clinical trials, a syringe and needle device has been used to inject living cells into the brain. Because cells do not spread through the brain tissue after implantation, multiple brain penetrations (more than ten separate needle insertions in some patients) have been required to distribute cells in the diseased brain region. Every separate brain penetration carries a significant risk of bleeding and brain injury. Furthermore, this approach does not result in effective distribution of cells. Thus, our lack of appropriate surgical tools and techniques for clinical cell transplantation represents a significant roadblock to the treatment of brain diseases with stem cell based therapies. A more ideal device would be one that can distribute cells to large and anatomically complex brain areas through a single initial brain penetration.
  • In the first year of progress, we designed, prototyped, and tested a stereotactic neurosurgical device capable of delivering cells to a volumetrically large target region through a single cortical brain penetration. We compared the performance of our device to a currently used cell transplantation implement – a 20G cannula with dual side ports. Through a single initial penetration, our device could transplant materials to a region greater than 4 cubic centimeters. Modeling with neurosurgical planning software indicated that our device could distribute cells within the entire human putamen – a target used in Parkinson’s disease trials – via a single transcortical penetration. While reflux of material along the penetration tract was problematic with the 20G cannula, resulting in nearly 80% loss of cell delivery, our device was resistant to reflux. We also innovated an additional system that facilitates small and precise volumes of injection. Both dilute and highly concentrated neural precursor cell populations tolerated transit through the device with high viability and unaffected developmental potential. Our device design is compatible with currently employed frame-based, frameless, and intraoperative MRI stereotactic (iMRI) neurosurgical targeting systems.
  • In this second year of progress, we have produced and tested the iMRI compatible version of our cell delivery device. The device components are fabricated from materials that are FDA-approved for use in medical devices, and we have assembled the device under Good Manufacturing Practice (GMP) conditions. Our device functions seamlessly with an FDA-approved stereotactic iMRI neurosurgical platform and computer-aided targeting system, and we have demonstrated that this iMRI-compatible system can deliver to the volume and shape of the human putamen through a single initial brain penetration. Thus, by using modern materials and manufacturing techniques, we have produced a neurosurgical device and technique that enables clinicians to “tailor” cell delivery to individual patient anatomical characteristics and specific disease states. This modern and “easy to use” platform technology furthermore allows “real-time” monitoring of cell delivery and unprecedented complication avoidance, increasing patient safety.
  • In this third year of progress, we have made final design refinements to the Radially Branched Deployment (RBD) cell transplantation device, which is fully compatible with currently employed interventional MRI stereotactic (iMRI) neurosurgical targeting systems. These design changes increase the "usability" of the device and enhance patient safety. The iMRI-guided RBD technology advances our ability to properly “tailor” the distribution of cell delivery to larger brain target volumes that vary in size and shape due to individual patient anatomy and different disease states. Furthermore, iMRI-guided RBD may increase patient safety by enabling intraoperative MRI monitoring. Importantly, this platform technology is easy-to-use and has a low barrier to implementation, as it can be performed “inside” essentially any typical diagnostic 1.5T MRI scanner found in most hospitals. We believe that this ease of access to the technology will facilitate the conduct of multi-site clinical trials and the future adoption of successful cellular therapies for patient care worldwide. In summary, by improving intracerebral cell delivery to the human brain, iMRI-guided RBD may have a transformative impact on the safety and efficacy of cellular therapeutics for a wide range of neurological disorders, helping ensure that basic science results are not lost in clinical translation.
  • Working with a California-based medical device manufacturer, we have developed manufacturing and testing procedures that are now being compiled into a design history file, which is a document required for eventual commercial use of the device. We are also working with an FDA regulatory consultant to prepare a 510K application to seek marketing clearance from the FDA.
  • We have developed a platform technology that enables Radially Branched Deployment (RBD) of cells to multiple target locations at variable radial distances and depths along the initial brain penetration tract with real-time interventional magnetic resonance image (iMRI) guidance. iMRI-guided RBD functions as an “add-on” to standard neurosurgical and imaging workflows, and procedures can be performed in a commonly available clinical MRI scanner. This new device has been demonstrated to be safe for procedures in large brains and functions at the scale of the human brain. Human embryonic stem cell-derived dopaminergic (hDA) neurons are compatible with the iMRI-guided RBD platform. Thus, iMRI-guided RBD overcomes some of the technical limitations inherent to the use of straight cannulas and standard stereotactic targeting. The device has been licensed to a California-based company, Accurexa, Inc., which is commercializing the technology for clinical use. This platform technology could have a major impact on the clinical translation of a wide range of cell therapeutics for the treatment of many neurological diseases.
Funding Type: 
hPSC Repository
Grant Number: 
IR1-06600
Investigator: 
ICOC Funds Committed: 
$9 999 834
Disease Focus: 
Developmental Disorders
Heart Disease
Infectious Disease
Alzheimer's Disease
Neurological Disorders
Autism
Respiratory Disorders
Vision Loss
Liver Disease
Epilepsy
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 

Critical to the long term success of the CIRM iPSC Initiative of generating and ensuring the availability of high quality disease-specific human IPSC lines is the establishment and successful operation of a biorepository with proven methods for quality control, safe storage and capabilities for worldwide distribution of high quality, highly-characterized iPSCs. Specifically the biorepository will be responsible for receipt, expansion, quality characterization, safe storage and distribution of human pluripotent stem cells generated by the CIRM stem cell initiative. This biobanking resource will ensure the availability of the highest quality hiPSC resources for researchers to use in disease modeling, target discovery and drug discovery and development for prevalent, genetically complex diseases.

Statement of Benefit to California: 

The generation of induced pluripotent stem cells (iPSCs) from patients and subsequently, the ability to differentiate these iPSCs into disease-relevant cell types holds great promise in facilitating the “disease-in-a-dish” approach for studying our understanding of the pathological mechanisms of human disease. iPSCs have already proven to be a useful model for several monogenic diseases such as Parkinson’s, Fragile X Syndrome, Schizophrenia, Spinal Muscular Atrophy, and inherited metabolic diseases such as 1-antitrypsin deficiency, familial hypercholesterolemia, and glycogen storage disease. In addition, the differentiated cells obtained from iPSCs represent a renewable, disease-relevant cell model for high-throughput drug screening and toxicology/safety assessment which will ultimately lead to the successful development of new therapeutic agents. iPSCs also hold great hope for advancing the use of live cells as therapies for correcting the physiological manifestations caused by disease or injury.

Progress Report: 
  • The California Institute for Regenerative Medicine (CIRM) Human Pluripotent Stem Cell Biorepository is operated by the Coriell Institute for Medical Research and is a critical component of the CIRM Human Stem Cell Initiative. The overall goal of this initiative is to generate, for world-wide use by non-profit and for-profit entities, high quality, disease-specific induced pluripotent stem cells (iPSCs). These cells are derived from existing tissues such as blood or skin, and are genetically manipulated in the laboratory to change into cells that resemble embryonic stem cells. iPSCs can be grown indefinitely in the Petri dish and have the remarkable capability to be converted into most of the major cell types in the body including neurons, heart cells, and liver cells. This ability makes iPSCs an exceptional resource for disease modeling as well as for drug screening. The expectation is that these cells will be a major benefit to the process for understanding prevalent, genetically complex diseases and in developing innovative therapeutics.
  • The Coriell CIRM iPSC Biorepository, located at the Buck Institute for Research on Aging in Novato, CA, is funded through a competitive grant award to Coriell from CIRM and is managed by Mr. Matt Self under the supervision of the Program Director, Dr. Steven Madore, Director of Molecular Biology at Coriell. The Biorepository will receive biospecimens consisting of peripheral blood mononuclear cells (PBMCs) and skin biopsies obtained from donors recruited by seven Tissue Collector grant awardees. These biospecimens will serve as the starting material for iPSC derivation by Cellular Dynamics, Inc (CDI). Under a contractual agreement with Coriell, CDI will expand each iPSC line to generate sufficient aliquots of high quality cryopreserved cells for distribution via the Coriell on-line catalogue. Aliquots of frozen cell lines and iPSCs will be stored in liquid nitrogen vapor in storage units at the Buck Institute with back-up aliquots stored in a safe off-site location.
  • Renovation and construction of the Biorepository began at the Buck Institute in late January. The Biorepository Manger was hired March 1 and after installation of cryogenic storage vessels and alarm validation, the first biospecimens were received on April 30, 2014. Additionally, Coriell has developed a Clinical Information Management System (CIMS) for storing all clinical and demographic data associated with enrolled subjects. Tissue Collectors utilize CIMS via a web interface to upload and edit the subject demographic and clinical information that will ultimately be made available, along with the iPSCs, via Coriell’s on-line catalogue
  • As of November 1 specimens representing a total of 725 unique individuals have been received at the Biorepository. These samples include PBMCs obtained from 550 unique individuals, skin biopsies from 72 unique individuals, and 103 primary dermal fibroblast cultures previously prepared in the laboratories of the CIRM Tissue Collectors. A total of 280 biospecimen samples have been delivered to CDI for the purpose of iPSC derivation. The Biorepository is anticipating delivery of the first batches of iPSCs for distribution in early 2015. These lines, along with the associated clinical data, will become available to scientists via the on-line Coriell catalogue. The CIRM Coriell iPSC Biorepository will ensure safe long-term storage and distribution of high quality iPSCs.

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