Introduction: Spinal cord injury (SCI) resulting in paraplegia or quadriplegia is a significant burden in the world. It is estimated that there are approximately 250,000 people living with SCI in the United States alone.Our study offered the direct implantation of human-derived stem cells into the spinal cord of subjects who suffer from chronic SCI. The primary objective of the study is to determine the safety and toxicity of human spinal stem cell transplantation for the treatment of paralysis. The secondary objectives of the study are to evaluate (1) graft survival in the transplant site (2) effectiveness of transient immunosuppression as determined by absence of donor-specific HLA antibodies (3) potential therapeutic role of implantation on motor and sensory function in SCI.

Methods: This is a Phase I, open-label, single-site, study of human spinal cord-derived neural stem cell (HSSC) transplantation for the treatment of chronic SCI.4 subjects with chronic SCI with ASIA A SCI who met eligibility criteria were enrolled.All subjects received spinal cord injections of HSSC.The treatment consisted of removal of spinal instrumentation followed by direct injections into spinal parenchyma. 6 HSSC injections were administered in each subject. Each injection consisted of 2 x 105 cells in 10µL.

Results: 4 subjects have been implanted to date.All subjects tolerated the procedure well and there have been no major adverse events to date. Prospective data has been collected including ISNCSCI scores, ASIA level, functional and pain surveys, SCIM scores, Sensory and Motor Evoked potentials, EMG, and MRI including a novel sequence of MR spinal diffusion tensor imaging (DTI). These metrics are continuing to be collected and evaluated.

Conclusions: We can conclude that (1) HSSC transplanted into the injury site of a spinal cord in chronic spinal cord injury patients can be done safely. (2)The HSSC graft has been shown to have no major adverse event to date.

Patient Care: The immediate short term relevancy of our clinical trial would be that we may prove or disprove our hypothesis that implantation of stem cells in human subjects is safe. If this is proven by our scientific method and they are proven to be safe, we will open the door for many more stem cell trials awaiting clinical research. Our goal is to provide a tangible treatment modality for those subjects who suffer from SCI and are relegated to a dismal diagnosis and even worse prognosis. In the longer term our trial has the potential to allow for increased study and clinical application of stem cell derived therapy in patients with spinal cord injury. This would be a revolutionary shift in the paradigm of treatment for SCI. It could transform SCI from a permanent disease with few to no treatment options, to one with a real therapy. There are currently no pharmacologic agents, devices or clinical applications available to this subset of patients. This is an area of current research that has true bench-to-bedside applications.

Learning Objectives: By the conclusion of this session, participants should be able to: 1) Describe the background, hypothesis, goal and results of our trial. 2) Understand and advance their own knowledge of current potential therapeutic options for patients with SCI. 3) Continue to understand how stem cell therapies and research may advance the field of neurological surgery and neural regeneration.

References: (Kakinohana et al., 2004, Marsala et al., 2004, Cizkova et al., 2007, Usvald et al., 2010, Kakinohana et al., 2012, Navarro et al., 2012, van Gorp et al., 2013) Cizkova D, Kakinohana O, Kucharova K, Marsala S, Johe K, Hazel T, Hefferan MP, Marsala M (2007) Functional recovery in rats with ischemic paraplegia after spinal grafting of human spinal stem cells. Neuroscience 147:546-560. Kakinohana O, Cizkova D, Tomori Z, Hedlund E, Marsala S, Isacson O, Marsala M (2004) Region-specific cell grafting into cervical and lumbar spinal cord in rat: a qualitative and quantitative stereological study. Exp Neurol 190:122-132. Kakinohana O, Juhasova J, Juhas S, Motlik J, Platoshyn O, Hefferan M, Yuan SH, Vidal JG, Carson CT, Galik J, van Gorp S, Leerink M, Lazar P, Marsala S, Miyanohara A, Goldberg D, Kafka J, Keshavarzi S, Ciacci JD, Marsala M (2012) Survival and differentiation of human embryonic stem cell-derived neural precursors grafted spinally in spinal ischemia-injured rats or in naive immunosuppressed minipigs: a qualitative and quantitative study. Cell Transplantation (in press). Marsala M, Kakinohana O, Yaksh TL, Tomori Z, Marsala S, Cizkova D (2004) Spinal implantation of hNT neurons and neuronal precursors: graft survival and functional effects in rats with ischemic spastic paraplegia. Eur J Neurosci 20:2401-2414. Navarro R, Juhas S, Keshavarzi S, Juhasova J, Motlik J, Johe K, Marsala S, Scadeng M, Lazar P, Tomori Z, Schulteis G, Beattie M, Ciacci JD, Marsala M (2012) Chronic spinal compression model in minipigs: a systematic behavioral, qualitative, and quantitative neuropathological study. J Neurotrauma 29:499-513. Usvald D, Vodicka P, Hlucilova J, Prochazka R, Motlik J, Strnadel J, Kucharova K, Johe K, Marsala S, Scadeng M, Kakinohana O, Navarro R, Santa M, Hefferan MP, Yaksh TL, Marsala M (2010) Analysis of dosing regimen and reproducibility of intraspinal grafting of human spinal stem cells in immunosuppressed minipigs. Cell Transplant 19:1103-1122. van Gorp S, Leerink M, Kakinohana O, Platoshyn O, Santucci C, Galik J, Joosten EA, Hruska-Plochan M, Goldberg D, Marsala S, Johe K, Ciacci JD, Marsala M (2013) Amelioration of motor/sensory dysfunction and spasticity in a rat model of acute lumbar spinal cord injury by human neural stem cell transplantation. Stem Cell Res Ther 4:57.