*E. S. ROSENZWEIG, J. H. BROCK, P. LU, H. KUMAMARU, J. L. WEBER, C. A. WEINHOLTZ, R. MOSEANKO, S. HAWBECKER, R. PENDER, C. L. CRUZEN, E. A. SALEGIO,, J. HUIE, C. ALMEIDA, Y. S. NOUT-LOMAS, L. A. HAVTON, A. R. FERGUSON, M. S. BEATTIE, J. C. BRESNAHAN, M. H. TUSZYNSKI
We previously demonstrated that human neural stem cells (hNSCs) and multipotent neural progenitor cells (hNPCs) grafted into sites of rodent spinal cord injury (SCI) survive, extend axons, form synapses, support host axon regeneration, and improve functional recovery (Lu et al., Cell 2012; Lu et al., Neuron 2014; Kadoya et al., Nat Med 2016). Recently, we published the first steps in translation of this approach to non-human primates using hNSCs derived from fetal tissue (Rosenzweig et al., Nat Med 2018).
We now discuss continued development of this approach, specifically addressing issues that will enable potential translation to human clinical trials. We have developed a human embryonic stem cell-derived neural stem cell line driven to a spinal cord identity (H9-scNSC; Kumamaru et al., Nat Methods 2018) as a candidate optimal cell type for human translation. In the present work, we have grafted this lead candidate translational cell line to rhesus monkeys that have undergone either C7 unilateral spinal cord hemisection (Rosenzweig et al., Nat Neurosci 2010) or C7 unilateral spinal cord contusion (Salegio et al., J Neurotrauma 2016). We find that:
1) H9-scNSC grafts placed into sites of C7 hemisection SCI survive, extend axons, form synapses, and support host axon regeneration. Analysis of possible graft-associated functional improvement is ongoing.
2) H9-scNSC grafts placed into sites of C7 unilateral contusion SCI survive, extend axons, form synapses, and support host axon regeneration. Analysis of possible graft-associated functional improvement is ongoing.
3) In the first subject maintained for 1.5 years after grafting, the graft survived, extended axons, and supported host axon regeneration. Critically, there was no sign of excessive graft growth or other safety problems.
*E. S. ROSENZWEIG1, J. H. BROCK1,2, P. LU1,2, H. KUMAMARU1, J. L. WEBER1, C. A. WEINHOLTZ1, R. MOSEANKO3, S. HAWBECKER3, R. PENDER3, C. L. CRUZEN3, E. A. SALEGIO3, J. HUIE4, C. ALMEIDA4, Y. S. NOUT-LOMAS5, L. A. HAVTON6, A. R. FERGUSON4,7, M. S. BEATTIE4, J. C. BRESNAHAN4, M. H. TUSZYNSKI1,2;
1Neurosciences, Univ. of California San Diego Dept. of Neurosciences, La Jolla, CA; 2VA Med. Ctr. San Diego, San Diego, CA; 3California Natl. Primate Res. Center, Univ. Calif. Davis, Davis, CA; 4Dept. of Neurolog. Surgery, Brain and Spinal Injury Ctr. (BASIC), UCSF, San Francisco, CA; 5Col. of Vet. Med. and Biomed. Sciences, Colo. State Univ., Fort Collins, CO; 6Dept. of Neurol., UCLA, Los Angeles, CA; 7VA Med. Ctr. San Francisco, San Francisco, CA. Continued development of human neural stem cell grafts into non-human primate spinal cord contusion or hemisection lesions. Program No. 138.11. 2018 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience, 2018. Online.
VA IP50RX001045 RR&D B7332R
NIH NCRR P51 OD011107-56
Craig H Neilsen Foundation
Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
Bernard and Anne Spitzer Charitable Trust
DOD CDMRP SC170233