Neurological Disorders

Coding Dimension ID: 
303
Coding Dimension path name: 
Neurological Disorders
Grant Type: 
Clinical Trial Stage Projects
Grant Number: 
CLIN2-12379
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$11 998 988
Disease Focus: 
Neurological Disorders
Stroke
Human Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 

Therapeutic Candidate or Device

A human embryonic derived, non-genetically modified neural stem cell (NR1), originally derived from the Wi-Cell H-9 line

Indication

Patients with chronic motor deficits, from 6 to 60 months after stroke. NR1 cells will be injected into the brain near the site of the stroke.

Therapeutic Mechanism

The proposed therapeutic mechanism of action of NR1 neural stem cells is the secretion of factors that enhance the brain’s own ability to heal itself after stroke, including the creation of new blood vessels to replace those that were injured beyond repair, and modulation of the immune system.

Unmet Medical Need

Strokes are a leading cause of adult disability. There is no medical therapy able to promote recovery in chronic stroke patients, establishing stroke as a major unmet medical need. NR1 cells will be the first stem cell-derived therapy directed towards improving disability for this disease.

Project Objective

Complete a Phase 1 / Phase 2a trial with analysis

Major Proposed Activities

  • Complete a Phase 1 / Phase 2a Clinical Trial for NR1 treatment after stroke and initial data analysis
  • Manufacture a cGMP NR1 working cell bank and clinical lot
  • Complete the potency assay and stability program development
Statement of Benefit to California: 

This program provides several areas of benefit to California as the first stem cell-derived therapy for recovery of function after stroke. It will provide medical benefits by treating disabled Californians. It will provide an economic benefit as a medical therapy that is manufactured and tested within the state. It will provide scientific benefit by pioneering the science of brain repair in California universities, with likely spin-off of additional novel therapies for neurological disease.

Grant Type: 
Clinical Trial Stage Projects
Grant Number: 
CLIN2-12319
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$11 990 372
Disease Focus: 
Amyotrophic Lateral Sclerosis
Neurological Disorders
Human Stem Cell Use: 
Adult Stem Cell
Public Abstract: 

Therapeutic Candidate or Device

CNS10-NPC-GDNF - a neural progenitor cell secreting GDNF

Indication

Amyotrophic Lateral Sclerosis (ALS)

Therapeutic Mechanism

This therapy will replace damaged astrocytes. The new astrocytes will release paracrine factors. As the cells have been modified to release GDNF they will also provide this neuroprotective factor to dying motor neurons in the motor cortex.

Unmet Medical Need

There are currently only two FDA-approved therapies with minimal benefits, but there is no cure for ALS. Thus there is a huge unmet medical need to find additional therapies with longer-lasting benefits.

Project Objective

Phase 1/2a completed

Major Proposed Activities

  • Enrollment of 16 patients to a Phase 1/2a trial to demonstrate safety and preliminary efficacy of the cellular product
  • GMP manufacturing of a new CNS10-NPC-GDNF working cell lot for future clinical trials in ALS.
Statement of Benefit to California: 

ALS is a devastating disease and there are over 6,000 cases in CA. If this treatment works it will provide one of the only ways to slow down motor neuron disease progression. This illness costs the state of California millions of dollars in healthcare costs and immense suffering to those Californians affected by the disease. Additionally, because over 90% of the funds will be used in California, it will help stimulate the economy.

Grant Type: 
Clinical Trial Stage Projects
Grant Number: 
CLIN2-12129
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$8 996 474
Disease Focus: 
Neurological Disorders
Spina Bifida
Human Stem Cell Use: 
Adult Stem Cell
Public Abstract: 

Therapeutic Candidate or Device

Allogeneic Placenta-derived Mesenchymal Stem Cells Seeded on Cook Biodesign® Dural Graft Extracellular Matrix (PMSC-ECM)

Indication

Myelomeningocele (MMC) -or Spina Bifida -diagnosed prenatally

Therapeutic Mechanism

Placenta-derived mesenchymal stem cells (PMSCs) act by a paracrine mechanism, secreting a variety of growth factors, cytokines, and extracellular vesicles. This secretory profile is unique to PMSCs and is responsible for protecting motor neurons from apoptosis, which occurs due to chemical and mechanical trauma when motor neurons are exposed to the intrauterine environment. PMSC treatment increases the density of motor neurons in the spinal cord, leading to improved motor function.

Unmet Medical Need

The current standard of care in utero surgery, while promising, still leaves 58% of patients unable to walk independently. There is an extraordinary need for a therapy that prevents or lessens the severity of the devastating and costly lifelong disabilities associated with the disease.

Project Objective

Phase 1 trial completed

Major Proposed Activities

  • Enrollment of 6 patients to demonstrate safety and preliminary efficacy of PMSC-ECM product
  • FDA-compliant manufacturing and testing studies of the PMSC-ECM product
Statement of Benefit to California: 

There is a high incidence of MMC in CA with 39.1% of the population being of Hispanic or Latino descent, a demographic that is affected by MMC at a disproportionately high rate. The cost to CA is approximately $532,000 per child, but for many, the cost may be several million dollars due to ongoing treatment. Indirect costs include pain and suffering, specialized childcare, and lost time of unpaid caregivers. A therapy for MMC would relieve the tremendous emotional and economic cost burden to CA.

Grant Type: 
Clinical Trial Stage Projects
Grant Number: 
CLIN2-11661
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$5 510 462
Disease Focus: 
Neurological Disorders
Parkinson's Disease
Human Stem Cell Use: 
Vital Research Opportunity
Public Abstract: 

Therapeutic Candidate or Device

AAV2-GDNF is a gene therapy product encoding Glial cell line-Derived Neurotrophic Factor (GDNF)

Indication

Parkinson's disease

Therapeutic Mechanism

AAV2-GDNF will be delivered into the putamen. GDNF is a growth factor expected to act by stimulating regeneration of the terminals of dopamine producing neurons that are progressively lost in PD. This is expected to result in an increase in dopamine production leading to improved motor and non-motor functions.

Unmet Medical Need

Current therapies such as L-DOPA and Deep Brain Stimulation help to alleviate the symptoms, but the loss of dopamine producing neurons continues, so they are progressively less effective. AAV2-GDNF is a disease-modifying approach, expected to slow and/or halt the progression of PD.

Project Objective

Phase 1b trial completed

Major Proposed Activities

  • Activation of California clinical site for recruitment and treatment of study subjects
  • Patient enrolment, randomization and dosing and completion of 18-month primary follow-up post-surgery.
  • Manufacturing of AAV2-GDNF for Phase 2/3 clinical studies, and drug comparability studies.
Statement of Benefit to California: 

The combined direct and indirect cost associated with PD, including treatments, social security payments, and loss of income is well over $25 billion/yr in the US with an expected increase of 60,000 patients per year. Given that California is the most populous state in the US, and has an ageing population, AAV2-GDNF therapy could hugely lower the socioeconomic consequences on its citizens.

Grant Type: 
Clinical Trial Stage Projects
Grant Number: 
CLIN2-09284
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$6 154 067
Disease Focus: 
Amyotrophic Lateral Sclerosis
Neurological Disorders
Human Stem Cell Use: 
Adult Stem Cell
Public Abstract: 

Therapeutic Candidate or Device

CNS10-NPC-GDNF - a neural progenitor cell secreting GDNF

Indication

ALS

Therapeutic Mechanism

This therapy will replace damaged astrocytes. The new astrocytes will release paracrine factors. As the cells have been modified to release GDNF they will also provide this factor to dying motor neurons.

Unmet Medical Need

There is no treatment or cure for ALS. Thus there is a huge unmet medical need.

Project Objective

Phase 1/2a clinical trial

Major Proposed Activities

Assess clinical safety of the therapeutic product

Statement of Benefit to California: 

ALS is a devastating disease and there are over 6,000 cases in CA. If this treatment works it will provide one of the only ways to slow down motor neuron disease progression. This illness costs the state of California millions of dollars in healthcare costs and immense suffering to those Californians affected by the disease.

Grant Type: 
Clinical Trial Stage Projects
Grant Number: 
CLIN2-10344
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$19 998 580
Disease Focus: 
Neurological Disorders
Stroke
Human Stem Cell Use: 
Adult Stem Cell
Public Abstract: 

Therapeutic Candidate or Device

Modified adult donor bone marrow-derived mesenchymal stem cells (Modified MSC)

Indication

Chronic motor deficit secondary to ischemic stroke

Therapeutic Mechanism

Local intracerebral delivery of Modified MSC adjacent to motor pathways stimulate via a paracrine mechanism neuropoiesis & angiogenesis by the release of FGF-2, other trophic factors & ECM proteins. The net effect is alteration of synaptic transmission appearing to improve motor function in a hitherto inhibitory milieu. Collectively, these properties are thought to promote neuroplasticity seen as the basis for improvement in motor function observed in stroke patients treated with Modified MSC.

Unmet Medical Need

There are no proven medical treatments available for chronic disability secondary to stroke. Results from our Phase 1/2a study suggest that Modified MSC has a favorable safety profile and the potential to improve motor function in these patients.

Project Objective

Complete Ph 2b trial; EOP2 meeting; Enable Phase 3

Major Proposed Activities

  • Completion of Phase 2b ACTIsSIMA clinical trial.
  • Manufacture Modified MSC clinical supplies.
  • Further investigate and validate the mechanisms of action to identify additional measures of potency and validation of associated bioassays.
Statement of Benefit to California: 

In 2012, 96,500 Californians suffered strokes with approximately 67,500 patients experiencing residual disabilities. Results from our Phase 1/2a study suggest that Modified MSC has a favorable safety profile and the potential to improve motor function in these Californians. This research will involve many clinical & research sites throughout California which will have a positive effect on the state’s economy and scientific profile.

Grant Type: 
Strategic Partnership III Track A
Grant Number: 
SP3A-07552
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$14 323 318
Disease Focus: 
Neurological Disorders
Spinal Cord Injury
Human 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.

Grant 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
Human 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.

Grant Type: 
Targeted Clinical Development
Grant Number: 
CT1-05168
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$24 846 856
Disease Focus: 
Neurological Disorders
Spinal Cord Injury
Human Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

The proposed project is designed to assess the safety and preliminary activity of escalating doses of human embryonic stem cell (hESC) derived oligodendrocyte progenitor cells for treatment of spinal cord injury. Oligodendrocyte progenitor cells have two important functions: they produce neurotrophic factors which stimulate the survival and growth of neurons (nerve cells) after injury, and they mature in the spinal cord to produce myelin, the insulation which envelops neuronal axons (nerve cell bodies responsible for conduction) and facilitates unimpeded nerve impulse conduction. After extensive efficacy and safety testing, clinical testing of this product was initiated in 2010.

Clinical testing is being initiated in paraplegic patients with neurologically complete thoracic injuries (i.e., those in which no motor or sensory function remains below the level of the injury). In the first cohort, a dose equivalent to the lowest efficacious dose observed in preclinical rodent studies is being administered. During the course of the proposed program, clinical safety studies testing increasing doses will be conducted. Upon demonstration of safety, clinical testing will be expanded to tetraplegic patients (complete cervical injuries) and to patients with incomplete thoracic injuries for additional safety testing. In each of the proposed studies, preliminary evidence of activity will be monitored using measures of improved neurological function and performance of daily living activities.

The project plan also includes the manufacture of cells to be used in the clinical trials and additional supporting activities. By completion of the proposed project, we expect to have accumulated substantial safety data and preliminary efficacy data in three different patient subpopulations. This data will provide key information to inform the design and execution of advanced efficacy studies.

Statement of Benefit to California: 

The proposed project has the potential to benefit the state of California through 1) providing improved medical outcomes for patients with spinal cord injury and their families, 2) increasing California’s leadership in the emerging field of stem cell research, and 3) preserving and creating high quality, high paying jobs for Californians.

Over 12,000 Americans suffer spinal cord injuries each year, and approximately 1.3 million people in the US are estimated to be living with spinal cord injuries. Although specific estimates for the state of California are not available, it is known that the majority of spinal cord injuries result from motor vehicle accidents, falls, acts of violence and recreational sporting activities, all of which are prevalent in California. Spinal cord injury affects not only the patient but family members, friends, healthcare workers and employers. It is estimated that one year after injury, only 11.6% of spinal cord injury patients are employed, and that spinal cord injuries cost $40.5 billion annually in the US. As the most populous state, California is disproportionately affected, negatively impacting our productivity, healthcare system and public finances. There are currently no approved therapies for the treatment of spinal cord injury. The product described in this application has initiated phase 1 clinical testing in patients with complete thoracic spinal cord injury. Even partial correction of any of the debilitating consequences of spinal cord injury could potentially enhance activities of daily living and increase employment while decreasing reliance on attendant care and subsequent medical interventions.

California has a history of leadership in biotechnology, and is emerging as a leader in the development of stem cell therapeutics. Cutting edge stem cell research, in many cases funded by CIRM, is already underway in academic research laboratories and biotechnology companies throughout the state. The proposed project has the potential to further increase California’s leadership in the field of stem cell therapeutics through the performance of the first clinical testing of an hESC-derived therapy.
The applicant has been located in California since its inception, and currently employs 182 full-time employees at its California headquarters with more than 50% of employees holding an advanced degree. These positions are highly skilled positions, offering competitive salaries and comprehensive benefits. The successful performance of the proposed project would enable significant additional jobs creation in preparation for pivotal trials and product registration.

Grant Type: 
Clinical Trial Stage Projects
Grant Number: 
CLIN2-09894
Investigator: 
Name: 
Type: 
PI
ICOC Funds Committed: 
$15 912 390
Disease Focus: 
Amyotrophic Lateral Sclerosis
Neurological Disorders
Human Stem Cell Use: 
Adult Stem Cell
Public Abstract: 

Therapeutic Candidate or Device

A cell therapy that delivers high levels of neurotrophic factors to the CNS

Indication

Amyotrophic lateral sclerosis (ALS) or Lou Gehrig Disease

Therapeutic Mechanism

The Cell therapy is aimed at providing high levels of neurotrophic factors directly to the CNS, to support the dying neurons

Unmet Medical Need

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease in which the degeneration and death of motor neurons (MNs) leads to weakness, paralysis and eventually respiratory failure . There remains a great unmet medical need for safe and effective treatments for people with ALS.

Project Objective

Phase 3 completed

Major Proposed Activities

  • Manufacturing of cell therapy product
  • Enrolling 200 patients for the study
  • Run clinical trial
Statement of Benefit to California: 

Manufacturing of the cell therapy product for all US medical centers participating in the study will be exclusively in California
The study will include 2 clinical sites in California that will enroll 80 Californian patients of the the total 200 patients in the study.

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