Disease Team Therapy Development - Research
$20 000 000
1.3 million Americans suffer chronically from spinal cord injuries (SCI); each year ~15,000 individuals sustain a new injury. For California, this means nearly 147,000 individuals are living with a SCI which can leave otherwise healthy individuals with severe deficits in movement, sensation, and autonomic function. Recovery after SCI is often limited, even after aggressive emergency treatment with steroids and surgery, followed by rehabilitation. The need to develop new treatments for SCI is pressing. We believe that stem cell therapies could provide significant functional recovery, improve quality of life, and reduce the cost of care for SCI patients. The goal of this Disease Team is to evaluate a novel cell therapy approach to SCI involving transplantation of human neural stem cells. In 2005, the FDA authorized the world’s first clinical testing of human neural stem cell transplantation into the CNS. Since then, our research team has successfully generated clinical grade human neural stem cells for use in three clinical trials, established a favorable safety profile that now approaches five years in some subjects and includes evidence of long-term donor-cell survival. Relevant to this Disease Team, the most recent study began testing human neural stem cells in thoracic spinal cord injury. The initial group of three patients with complete injury has been successfully transplanted. The Disease Team seeks to extend the research into cervical SCI. Neural cell transplantation holds tremendous promise for achieving spinal cord repair. In preliminary experiments, the investigators on this Disease Team showed that transplantation of both murine and human neural stem cells into animal models of SCI restore motor function. The human neural stem cells migrate extensively within the spinal cord from the injection site, promoting new myelin and synapse formation that lead to axonal repair and synaptic integrity. Given these promising proof-of-concept studies, we propose to manufacture clinical-grade human neural stem cells and execute the preclinical studies required to submit an IND application to the FDA that will support the first-in-human neural stem cell transplantation trial for cervical SCI. Our unmatched history of three successful regulatory submissions, extensive experience in manufacturing, preclinical and clinical studies of human neural stem cells for neurologic disorders, combined with an outstanding team of basic and clinical investigators with expertise in SCI, stem cell biology, and familiarity with all the steps of clinical translation, make us an extremely competitive applicant for CIRM’s Disease Team awards. This award could ultimately lead to a successful FDA submission that will permit human testing of a new treatment approach for SCI; one that could potentially reverse paralysis and improve the patient’s quality of life.
Statement of Benefit to California:
Spinal cord injuries affect more than 147,000 Californians; the majority are injuries to the cervical level (neck region) of the spinal cord. SCI exacts a devastating toll not only on patients and families, but also results in a heavy economic impact on the state: the lifetime medical costs for an individual with a SCI can exceed $3.3 million, not including the loss of wages and productivity. In California this translates to roughly $86 billion in healthcare costs. Currently there are no approved therapies for chronic thoracic or cervical SCI. We hope to advance our innovative cell therapy approach to treat patients who suffer cervical SCI. For the past 9 years, the assembled team (encompassing academic experts in pre-clinical SCI models, complications due to SCI, rehabilitation and industry experts in manufacturing and delivery of purified neural stem cells), has developed the appropriate SCI models and assays to elucidate the therapeutic potential of human neural stem cells for SCI repair. Human neural stem cell transplantation holds the promise of creating a new treatment paradigm. These cells restored motor function in spinal cord injured animal models. Our therapeutic approach is based on the hypothesis that transplanted human neural stem cells mature into oligodendrocytes to remyelinate demyelinated axons, and/or form neurons to repair local spinal circuitry. Any therapy that can partially reverse some of the sequelae of SCI could substantially change the quality-of-life for patients by altering their dependence on assisted living, medical care and possibly restoring productive employment. Through CIRM, California has emerged as a worldwide leader in stem cell research and development. If successful, this project would further CIRM’s mission and increase California’s prominence while providing SCI therapy to injured Californians. This Team already has an established track record in stem cell clinical translation. The success of this Disease Team application would also facilitate new job creation in highly specialized areas including cell manufacturing making California a unique training ground. In summary, the potential benefit to the state of California brought by a cervical spinal cord Disease Team project would be myriad. First, a novel therapy could improve the quality of life for SCI patients, restore some function, or reverse paralysis, providing an unmet medical need to SCI patients and reducing the high cost of health care. Moreover, this Disease Team would maintain California’s prominence in the stem cell field and in clinical translation of stem cell therapies, and finally, would create new jobs in stem cell technology and manufacturing areas to complement the state’s prominence in the biotech field.
This proposal is to develop human neural stem cells (NSCs) to treat chronic cervical spinal cord injury (SCI). The applicant proposes to complete IND-enabling preclinical studies and file an IND within the four-year award period. This project would represent the first-in-human neural stem cell transplantation trial for cervical SCI. Significance and Impact - Most SCI patients have cervical injuries, so there is a substantial unmet clinical need. Even small gains in function can yield significant quality of life improvements. - This is a clinically competitive product, and there is a clear need for new and more effective therapies to minimize or improve neurologic dysfunction following SCI. - This proposal is for IND-enabling studies for the use of cell-based therapy following SCI and is responsive to the scope of this RFA. Rationale - The rationale is well thought out. Careful consideration has been made in the selection of regional injury and clinical endpoints with higher likelihood for detection and proof of mechanism. - The therapeutic cells have been shown to differentiate to multiple cell types in the spinal cord. - Although reviewers did not find the preliminary data compelling, they agreed that even small incremental steps can have a significant improvement in patients’ quality of life. - Some reviewers felt that the progression to human safety trials should have also included the use of large animal studies to enable assessment of factors that include cell migration and biodistribution. - Some reviewers expressed concerns that there are no large animal model studies proposed to test certain aspects of the cell delivery technique. - One reviewer questioned the preclinical design, noting that the project relies on translation of findings in rodents with incomplete injuries to those in humans with cervical injury, and raised concerns as to whether the human cervical injuries are severe enough to warrant the risks of invasive cell transplantation. Therapeutic Development Readiness -Reviewers were enthusiastic that the same cells have already been used in clinical trials, thus the ability to manage a Master Cell Bank (MCB) and Working Cell Bank (WCB) has been demonstrated. However, the rationale behind the need for a new cell bank was unclear. - Reviewers agreed that prior clinical experience and preliminary discussions with regulatory authorities reflects a mature and experienced launching point for the proposed clinical study, and represent a major strength of this application. - The role of the previously completed GLP studies in developing the IND is unclear. Feasibility of the Project Plan -Well thought out and feasible research plan. Reviewers agreed that the feasibility is high since the same cells are already in the clinic for other indications, including thoracic SCI. - Reviewers noted that there is work proposed in both sub-acute and chronic models, which the FDA will view as separate indications. Reviewers recommended focusing on the chronic indication and eliminate the proposed studies in acute injury. Principal Investigator (PI) and Development Team - This is an experienced team that has demonstrated the ability to move a therapeutic into clinical trials. - The organization of the team is well thought out and divided into the Stem Cell Biology component and the SCI pre-clinical studies component. - There was some concern that the team did not appear to include anyone with experience injecting into the cervical spinal cord, which is very technically challenging. Collaborations, Resources and Environment - Collaboration with a leading academic spinal cord injury lab was viewed as a strength of the application. - A strong IP portfolio has been established around the cell line being used in these studies; however, there was no discussion regarding possible concerns over freedom to operate. - The institutions involved are well equipped to perform these studies. Budget (Assessment of the budget was conducted separately from the overall scientific evaluation and points or concerns raised in this section did not contribute to the scientific score. This section highlights items that must be addressed should the application be approved for funding. ) - Matching funds have been committed to the project. - The budgets proposed for IND preparation and for report writing were viewed as excessive. - Reviewers noted that CIRM should not support work proposed on acute injury. - Reviewers noted that manufacturing costs and some preclinical study costs seemed excessive in light of the ongoing trial. Some costs may be duplicative with ongoing efforts so redundant costs without justification should be eliminated. It was unclear why equipment for toxicology studies was necessary.
- David Pepperl
- Lauren Black
- Mark Noble