Grants Working Group Recommendation

RFA 10-03 CIRM Targeted Clinical Development Awards

CT1-05168

Recommendation: Recommended for Funding
Total Funds Requested: $24,846,900

Applicant-provided 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.

Applicant-provided Statement of Benefit

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.

Project Synopsis

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. There are currently no approved therapies for the treatment of spinal cord injury.

This application proposes to treat spinal cord injury (SCI) with oligodendrocyte progenitor cells derived from human embryonic stem cells (hESCs). Oligodendrocyte progenitor cells produce neurotrophic factors which stimulate the survival and growth of neurons after injury, and following maturation in the spinal cord, they produce myelin, which provides the insulation required by neuronal axons to facilitate unimpeded nerve impulse conduction. After spinal cord injury, oligodendrocytes die as a result of the primary injury and secondary inflammation. The applicants propose that transplantation of oligodendrocyte progenitors will lead to a supply of neurotrophic factors to promote tissue sparing and repair, and possibly also to remyelination of denuded axons.

The proposed project aims to assess the safety and preliminary activity of escalating doses of hESC-derived oligodendrocyte progenitors in patients with different levels and severity of sub-acute spinal cord injury (SCI). An initial Phase I clinical trial has begun in which oligodendrocyte progenitors will be administered to subjects with neurologically complete thoracic SCI. After demonstrating safety in the first study cohort, the applicant intends to explore higher doses of oligodendrocyte progenitors as well as to expand clinical testing to include patients with complete cervical and incomplete thoracic injuries. By the end of the proposed 3-year project, the applicant expects to have safety data and preliminary evidence of activity in three patient populations, those with complete thoracic, complete cervical, or incomplete thoracic spinal cord injuries. The project plan also includes supporting manufacturing activities.

Review Criteria

The review panel considered the following review criteria as described in RFA 10-03:

1. Significance and Impact of the proposed project, including whether it could meet the objectives of the RFA, which are to evaluate preliminary safety in humans and provide evidence of mechanism in humans as well as preliminary evidence of clinical efficacy, within 3 years;
2. Project Design and Feasibility;
3. Qualifications and Experience of the Principal Investigator (PI) and Team; and
4. Collaborations, Assets, Resources and Environment.