Functional Neural Relay Formation by Human Neural Stem Cell Grafting in Spinal Cord Injury

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.