Spinal Cord Injury

Coding Dimension ID: 
315
Coding Dimension path name: 
Neurological Disorders / Spinal Cord Injury
Disease Fact Sheet Page: 
/our-progress/disease-information/spinal-cord-injury-fact-sheet
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: 
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: 
Quest - Discovery Stage Research Projects
Grant Number: 
DISC2-13020
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$789 000
Disease Focus: 
Neurological Disorders
Spinal Cord Injury
Human Stem Cell Use: 
iPS Cell
Public Abstract: 

Research Objective

We propose to develop and validate a therapy for spinal cord injuries in which human stem cell-derived neural cells is injected into the injured spinal cord using an injectable gel.

Impact

Our study will address the critical need for an SCI treatment that significantly improves the neurological recovery and hence quality of life of SCI patients and their caretakers.

Major Proposed Activities

  • We will determine if delivering human iPSC-derived neural cells within our injectable gels will improve its ability to graft into and regenerate the injured spinal cord, as compared to saline.
  • We will evaluate if the differences observed in Activity 1 is correlated to differences observed in the functional improvement of the different treatment groups.
  • Using multiple stem cell clones from the same donor as well as from distinct donors, we will evaluate what fraction of clones can pass multiple quality control criteria.
  • We will evaluate if distinct stem cell clones from different individuals can yield similar functional benefits when used to treat spinal cord injuries in rodents.
  • We will evaluate if different stem cell clones from the same individual can yield similar functional benefits when used to treat spinal cord injuries in rodents.
Statement of Benefit to California: 

An estimated 17,900 cases of spinal cord injury are diagnosed in the United States annually, with an estimated lifetime cost of at least $1,217,266 per patient. As the state with the largest population number, California is most significantly affected by SCIs. The success of our proposed research will significantly improve neurological and functional recovery in these patients, enhancing their quality of life, and reducing the economic and public health burden of the disease.

Grant Type: 
Quest - Discovery Stage Research Projects
Grant Number: 
DISC2-10753
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$1 575 613
Disease Focus: 
Neurological Disorders
Spinal Cord Injury
Human Stem Cell Use: 
Adult Stem Cell
Cell Line Generation: 
Adult Stem Cell
Public Abstract: 

Research Objective

This project generates new cGMP compliant tissue educated human neural stem cell lines, paired with in vivo pre-clinical proof of concept testing, and development of a predictive in vitro profile.

Impact

Identification of new cell lines with in vivo efficacy testing to enable efficient translation to chronic cervical spinal cord injury, an area of significant unmet medical need.

Major Proposed Activities

  • Derivation of new human neural stem cell lines
  • In vitro characterization of human neural stem cell lines
  • Construction of an in vitro cell line profile that can discriminate in vivo efficacy potential
  • In vivo analysis of human neural stem cell line efficacy after transplantation into spinal cord injured mice
Statement of Benefit to California: 

The impact of this research includes generation of new CD133-enriched tissue-educated cGMP compliant human neural stem cell lines, which have demonstrated capacity for translation into the clinical for multiple neurological disorders, and development of a profile that can relate in vitro expression analyses from these cells under growth and differentiation conditions to in vivo efficacy. Both of these are critical steps for effective translation.

Grant Type: 
Quest - Discovery Stage Research Projects
Grant Number: 
DISC2-10665
Investigator: 
ICOC Funds Committed: 
$2 100 581
Disease Focus: 
Neurological Disorders
Spinal Cord Injury
Human Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 

Research Objective

We propose to utilize human neural stem cells to form neuronal relays across sites of severe SCI, restoring function across the site of spinal cord injury.

Impact

We will develop a specific type of neural stem cell that is best suited for repairing the injured spinal cord.

Major Proposed Activities

  • In Vitro Assessment of GMP-compatible H9-scNSC Batches.
  • In Vivo Assessment of GMP-compatible H9-scNSC Batches.
  • In Vivo Assessment of Disease Modifying Activity over time, Model 1: T10 moderate contusion.
  • In Vivo Assessment of Disease Modifying Activity over time, Model 2: T3 severe compression.
  • In Vivo Assessment of Disease Modifying Activity over time, Model 1: C5 moderate contusion.
  • FDA Pre-pre IND Meeting.
Statement of Benefit to California: 

Spinal cord injury (SCI) affects approximately 300,000 people in the U.S., with more than 11,000 new injuries per year. This research plan will examine a novel therapeutic strategy for SCI. Neural stem cells will be generated from human embryonic stem cells and grafted into animal models of SCI. We predict neuronal relays will form across a SCI lesion site that will mediate behavioral recovery. These studies will form the basis for clinical translation for the treatment of spinal cord injury.

Grant Type: 
Quest - Discovery Stage Research Projects
Grant Number: 
DISC2-08982
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$1 848 462
Disease Focus: 
Neurological Disorders
Spinal Cord Injury
Human Stem Cell Use: 
Embryonic Stem Cell
iPS Cell
Public Abstract: 

Research Objective

The goal of this proposal is to develop an optimized, scalable process to manufacture high quality oligodendrocyte precursor cells (OPCs) from human pluripotent stem cells for treating human disease.

Impact

OPCs have therapeutic potential for spinal cord injury, restoration of cognitive function after cancer radiation therapy, inherited demyelinating disease, and potentially multiple sclerosis.

Major Proposed Activities

  • To engineer human embryonic stem cell lines with fluorescent protein reporters to quantify differentiation into oligodendrocyte precursor cells (OPCs).
  • To use a high throughput system to screen thousands of cell culture conditions and thereby optimize a chemically-defined three-dimensional culture for differentiation into OPCs.
  • To validate the capacity of the differentiated oligodendrocyte precursor cells to remyelinate neurons in culture and in the nervous system.
  • To scale up this cell manufacturing system in a bioreactor for future translation towards preclinical and clinical studies.
Statement of Benefit to California: 

This proposal will accelerate the development of a stem cell therapy to treat patients with demyelinating conditions, a serious unmet medical need. Also, the PI has a strong record of translating research towards clinical development within industry, particularly within California. Finally, this project will expose young scientists within a large stem cell center to highly interdisciplinary training at the interface of science and engineering, thereby enhancing our California workforce.

Grant Type: 
Therapeutic Translational Research Projects
Grant Number: 
TRAN1-13059
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$5 552 611
Disease Focus: 
Neurological Disorders
Spinal Cord Injury
Human Stem Cell Use: 
Adult Stem Cell
Public Abstract: 

Translational Candidate

The therapeutic candidate is a central nervous system tissue-derived GMP line developed under DISC2-10753 with an established GMP qualified seed bank.

Area of Impact

The target is chronic cervical spinal cord injury, which represents approximately 59% of clinical spinal cord injury cases.

Mechanism of Action

Integration of transplanted human neural stem cells is likely to direct improved locomotor function by a combination of mechanisms that include the production of new myelinating cells. Transplanted neural stem cell survival, migration, and formation of new oligodendrocytes have been linked to repair capacity.

Unmet Medical Need

There are no FDA approved treatments for spinal cord injury. There are roughly 285,000 individuals living with paralysis due to traumatic spinal cord injury in the USA, with as many as 20,425 in California at a projected collective lifetime cost of $104 billion in direct and indirect costs of care.

Project Objective

Submission of a Pre-IND and Pre-IND meeting.

Major Proposed Activities

  • Establish critical process parameters for therapeutic candidate expansion and establish GMP final product bank.
  • Complete pre-clinical testing of final product cells and conduct preliminary testing of assays for potency and comparability during cell production.
  • Test a clinical strategy to improve engraftment and reduce rejection after allogeneic cell transplantation into the central nervous system.
Statement of Benefit to California: 

We seek to develop a new human neural stem cell therapeutic for chronic cervical spinal cord injury, for which there are no approved treatments. Improvement of a single level of spine function could have a large effect, significantly impacting both quality of life and the economic burden of disease. We also seek to develop new clinical strategies for monitoring potency during cell production and allogeneic cell transplantation, broadly impacting cell based therapies for neurological conditions.

Grant Type: 
Tools and Technologies III
Grant Number: 
RT3-07948
Investigator: 
Institution: 
Type: 
PI
Institution: 
Type: 
Co-PI
ICOC Funds Committed: 
$1 452 708
Disease Focus: 
Neurological Disorders
Spinal Cord Injury
Human Stem Cell Use: 
iPS Cell
Public Abstract: 

One critical bottleneck in the translation of regenerative medicine into the clinic is the efficient delivery and engraftment of transplanted cells. While direct injection is the least invasive method for cell delivery, it commonly results in the survival of only 5-20% of cells. Studies suggest that delivery within a carrier gel may enhance cell viability, but most of the gels used previously were naturally derived materials that have complex and unknown compositions. In our previous CIRM-funded work, we discovered that pre-encapsulating cells in very weak hydrogels offers the best protection during injection; however, those gels may be too compliant to support long-term cell survival. To address these limitations, we propose the design of a fully defined, customizable, and injectable material that initially forms a weak gel that then stiffens post-injection. We focus our studies on the delivery of human induced pluripotent stem cell-derived neural progenitors for the treatment of spinal cord injury (SCI). There are ~12,000 new SCI patients in the US each year, primarily young adults. SCI commonly results in paralysis, and the estimated lifetime cost for a patient can rise above $4 million dollars. In preclinical models of SCI, stem cell therapies have resulted in partial regeneration; however, reproducible delivery and engraftment of sufficient cells remain difficult and unmet challenges. This award potentially develops transformational regenerative therapies for SCI.

Statement of Benefit to California: 

The annual incidence of spinal cord injuries (SCI) in the United States is estimated at 12,000 new cases per year, with motor vehicle crashes accounting for up to a third of these cases. SCI has devastating impacts not only on the quality of life for the victims and their families, but also on their economic security – the estimated lifetime cost of an SCI patient can rise to over $4 million dollars depending on the severity and age at which the injury was sustained, not including the loss of wages and productivity. Although the most prevalent types of SCIs are those sustained at either the cervical or thoracic vertebrae, there are currently no definitive therapies approved for the chronic management of these SCI. Stem cell-based therapies have recently been shown to be mildly successful in several clinical and pre-clinical trials in various injuries and diseases, and a number of trials are ongoing for applications in SCI. In our proposal, we seek to advance the stem cell-based approach to the treatments of SCI. The potential benefit of this proposal to the state of California and its citizens include 1) the provision of a better medical prognosis for patients with spinal cord injuries, 2) the improved quality of life for SCI patients and their families, 3) the reduction of the burden of health care costs, 4) the creation and maintenance of jobs in the stem cell technology field, and 5) preserving California’s prominence in the field of stem cell research.

Grant 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
Human 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.

Grant Type: 
Basic Biology V
Grant Number: 
RB5-07320
Investigator: 
ICOC Funds Committed: 
$598 367
Disease Focus: 
Neurological Disorders
Spinal Cord Injury
Human Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

Our goal is to use the mechanisms that generate neuronal networks to create neurons from stem cells, to either replace diseased and damaged tissue or as a source of material to study disease mechanisms. A key focus of such regenerative studies is to restore function to the spinal cord, which is particularly vulnerable to damage. However, although considerable progress has been made in understanding how to direct stem cells towards motor neurons that control coordinated movement, little progress has been made so far directing stem cells to form the sensory neurons that allow us to experience the environment around us.

Our proposed research will use insights from the mechanisms known to generate the sensory neurons during the development of the spinal cord, to derive these neurons from stem cells. We will initially use mouse embryonic stem cells in these studies, to accelerate the experimental progress. We will then apply our findings to human embryonic stem cells, and assess whether these cells are competent to repopulate the spinal cord. These studies will significantly advance our understanding of how to generate the full repertoire of neural subtypes necessary to repair the spinal cord after injury, specifically permitting patients to recover sensations such as pain and temperature. Moreover, they also represent a source of therapeutically beneficial cells for modeling debilitating diseases, such as the chronic insensitivity to pain.

Statement of Benefit to California: 

Millions of Californians live with compromised nervous systems, damaged by either traumatic injury or disease. These conditions can be devastating, stripping patients of their ability to move, feel and think, and currently have no cure. As well as being debilitating for patients, living with these diseases is also extremely expensive, costing both Californians and the state of California many billions of dollars. For example, the estimated lifetime cost for a single individual managing spinal paralysis is estimated to be up to $3 million.

Stem cell technology offers tremendous hope for reversing or ameliorating both disease and injury states. Stem cells can be used to replenish any tissue damaged by injury or disease, including the spinal cord, which is particularly vulnerable to physical damage. Our proposed studies will develop the means to produce the spinal sensory neurons that permit us to perceive the environment. We will also determine whether these in vitro derived sensory neurons are suitable for transplantation back into the spinal cord. The generation of these neurons will constitute an important step towards reversing or ameliorating spinal injuries, and thereby improve the productivity and quality of life of many Californians. Moreover, progress in this field will solidify the leadership role of California in stem cell research and stimulate the future growth of the biotechnology and pharmaceutical industries within the state.

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