We aim to develop a novel stem cell treatment for spinal cord injury (SCI) that is substantially more potent than previous stem cell treatments. By combining grafts of neural stem cells with scaffolds placed in injury sites, we have been able to optimize graft survival and filling of the injury site. Grafted cells extend long distance connections with the injured spinal cord above and below the lesion, while the host spinal cord also sends inputs to the neural stem cell implants. As a result, new functional relays are formed across the lesion site. These result in substantially greater functional improvement than previously reported in animal studies of stem cell treatment. Work proposed in this grant will identify the optimal human neural stem cells for preclinical development. Furthermore, in an unprecedented step in spinal cord injury research, we will test this treatment in appropriate preclinical models of SCI to provide the greatest degree of validation for human translation. Successful findings could lead to clinical trials of the most potent neural stem cell approach to date.
Spinal cord injury (SCI) affects approximately 1.2 million people in the United States, and there are more than 11,000 new injuries per year. A large number of spinal cord injured individuals live in California, generating annual State costs in the billions of dollars. This research will examine a novel stem cell treatment for SCI that could result in functional improvement, greater independence and improved life styles for injured individuals. Results of animal testing of this approach to date demonstrate far greater functional benefits than previous stem cell therapies. We will generate neural stem cells from GMP-compatible human embryonic stem cells, then test them in the most clinically relevant animal models of SCI. These studies will be performed as a multi-center collaborative effort with several academic institutions throughout California. In addition, we will leverage expertise and resources currently in use for another CIRM-funded project for ALS, thereby conserving State resources. If successful, these studies will form the basis for clinical trials in a disease of great unmet medical need, spinal cord injury. Moreover, the development of this therapy would reduce costs for clinical care while bringing novel biomedical resources to the State.
In the first 12 months of this project we have made important progress in the following areas:
1) Identified the lead embryonic stem cell type for potential use in a translational clinical program.
2) Replicated the finding that implants of ES-derived neural progenitor cells from this lead cell type extend axons out from the spinal cord lesion site in very high numbers and over very long distances.
3) Begun efforts to scale this work to larger animal models of spinal cord injury.
Very good progress has been made in the last year on this project. We are attempting to address a great unmet medical need to develop effective therapies for human spinal cord injury (SCI). We aim to develop and optimize a pluripotent neural stem cell line for grafting to sites of spinal cord injury, and develop this line for clinical translation. Unlike other programs of stem cell therapy for SCI, we are transplanting neural stem cells directly into the injury site, in high numbers, and we observe very extensive growth of axons both into and out of the graft. The amount of axon growth in this model is substantially greater than that observed with other approaches to the injured spinal cord, including approaches currently in clinical trials. Accordingly, we believe that our approach provides a substantially greater opportunity to improve outcomes after SCI.
In the last year, we have identified a lead stem cell line for potential human translation, and validated its ability to engraft to the injured spinal cord. We have observed that human neural stem cells, grafted into mice and rats, exhibit a human time frame for maturation and growth: cells require at least one year to develop and mature. This knowledge is very important for planning human clinical trials.
Remaining work will characterize the long term safety and efficacy of these cells in rodent and large animal models of SCI.
The original objective of this study was to determine whether grafts of human NSCs to sites of SCI was safe, effective and worthy of human translation. We found that the lead candidate cell line, the UCSF4-NSC line, did not exhibit adequate long-term in vivo safety properties. However, an alternative cell line, the H9-NSC line, does exhibit favorable safety. We also identified for the first time that human NSCs exhibit a very prolonged, human temporal course of maturation in vivo, a finding with great implications for the design and performance of human clinical trials of NSCs for any neurological indication. Finally, we developed extremely important methods for the practical implementation of NSC transplantation to SCI lesion sites in humans.
While this specific program proposing to develop the UCSF4-NSC cell line for SCI will not move forward into patients, we are solidly on track for translating the H9-NSC line to potential human clinical trials. Moving forward, we propose to repeat several of the studies conducted in the Early Translational Award with the superior H9-NSC line. Studies funded during this Early Translational Award were essential in enabling the discoveries and insights that are propelling this program forward in a modified direction compared to the original proposal. We await review of a submitted TRAN1 grant proposal to determine whether this promising work will indeed continue. We are grateful to the dedicated staff at CIRM, and to the citizens of the State of California, for enabling and funding this work.