Introduction: Human CNS stem cells (HuCNS-SC) are non-tumorigenic, differentiate into neurons and oligodendrocytes, and have shown promise of locomotor recovery in murine spinal cord injury (SCI) models. A PH I/II trial in chronic thoracic SCI with HuCNS-SC showed favorable results.

Methods: A randomized, controlled, single-blind, multicenter PH II study was initiated to assess safety and efficacy of upper extremity function after HuCNS-SC transplantation in chronic cervical SCI (4-24 months post-injury, C5-7 motor, AIS A/B with <5 cm lesions on MRI). The study included an open-label dose-escalation arm (Cohort 1; n=6; from 15 to 40 million (M) cells) to select the cell dose for testing in the randomized controlled arm (Cohort 2; N=25; randomized to treatment (40 M cells) or control). Treatment consisted of manual intramedullary injection of cells above and below the injury epicenter and 6-months of immunosuppression medication. Standardized SCI motor and sensory assessments including ISNCSCI and GRASSP were utilized, along with recording of adverse events (AEs), MRI, pain and spasticity.

Results: Across the 17 transplanted subjects, 133 AEs were reported. AEs were mostly related to surgery, immunosuppression medication, and the underlying SCI, but no safety concerns related to the manual intramedullary injection of the cells. Day 1 post–op cervical spinal MRIs demonstrated mild increased T2 signal (n=8/17) without motor decrements, all of which resolved by 6-months post-transplant. One-year Cohort 1 data demonstrated overall safety and in 4 subjects, motor strength and functional improvement from baseline. Interim analysis of Cohort 2 showed greater motor gains in the treated subjects, but at a magnitude below the required clinical efficacy threshold set by the sponsor to support further development resulting in early study termination.

Conclusions: The overall safety of intramedullary transplantation of HuCNS-SC and evidence of biological activity support continued investigation of neural stem cells in chronic cervical SCI.

Patient Care: The development of regenerative strategies to improve the motor, sensory and functional outcomes of patients with chronic cervical spinal cord injury are needed and the current research gives us data on the possible and safety and efficacy of neural stem cell transplantation.

Learning Objectives: By the conclusion of this session, participants should be able to understand the surgical safety profile and feasibility of multiple intramedullary perilesional injections of HuCNS-SC after chronic cervical spinal cord injury. They should be able to discuss in small groups the preliminary efficacies seen in cohorts 1 and 2 after transplantation. They should also be able to identify that this form of therapy may be an effective means of improving functional outcomes after chronic cervical spinal cord injury and deserves further investigation.

References: Cummings BJ, Uchida N, Tamaki SJ, Salazar DL, Hooshmand M, Summers R, Gage FH, Anderson AJ. Human neural stem cells differentiate and promote locomotor recovery in spinal cord-injured mice. Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):14069-74. Epub 2005 Sep 19. Cummings BJ, Uchida N, Tamaki SJ, Anderson AJ. Human neural stem cell differentiation following transplantation into spinal cord injured mice: association with recovery of locomotor function. Neurol Res. 2006 Jul;28(5):474-81.