Disease modifying treatment of spinal cord injury with directly reprogrammed neural precursor cells in non-human primates

Vladimir P Baklaushev; Oleg V Durov; Vladimir A Kalsin; Eugene V Gulaev; Sergey V Kim; Ilya L Gubskiy; Veronika A Revkova; Ekaterina M Samoilova; Pavel A Melnikov; Dzhina D Karal-Ogly; Sergey V Orlov; Alexander V Troitskiy; Vladimir P Chekhonin; Alexander V Averyanov; Jan-Eric Ahlfors

doi:10.4252/wjsc.v13.i5.452

Disease modifying treatment of spinal cord injury with directly reprogrammed neural precursor cells in non-human primates

World J Stem Cells. 2021 May 26;13(5):452-469. doi: 10.4252/wjsc.v13.i5.452.

Authors

Affiliations

¹ Biomedical Research, Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies, FMBA of Russia, Moscow 115682, Moskva, Russia. serpoff@gmail.com.
² Department of Neurosurgery, Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies, FMBA, Moscow 115682, Moskva, Russia.
³ Biomedical Research, Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies, FMBA of Russia, Moscow 115682, Moskva, Russia.
⁴ Department of Anesthesiology, N.N.Blokhin Russian Cancer Research Centre, Moscow 115478, Moskva, Russia.
⁵ Ilya L Gubskiy, Radiology and Clinical Physiology Scientific Research Center, Federal center of brain research and neurotechnologies of the Federal Medical Biological Agency, Moscow 117997, Russia.
⁶ Department of Neurobiology, Serbsky National Medical Research Center for Psychiatry and Narcology, Moscow 119992, Moskva, Russia.
⁷ Department of Primatology, Russian Acad Med Sci, Research Institute of Medical Primatology, Sochi 119992, Sochi, Russia.
⁸ Department of Vascular Surgery, Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies, FMBA of Russia, Moscow 115682, Moskva, Russia.
⁹ Department of Basic and Applied Neurobiology, V.P. Serbsky Federal Medical Research Center for Psychiatry and Narcology, Russia.
¹⁰ New World Laboratories, Laval H7V 4A7, Quebec, Canada.

Abstract

Background: The development of regenerative therapy for human spinal cord injury (SCI) is dramatically restricted by two main challenges: the need for a safe source of functionally active and reproducible neural stem cells and the need of adequate animal models for preclinical testing. Direct reprogramming of somatic cells into neuronal and glial precursors might be a promising solution to the first challenge. The use of non-human primates for preclinical studies exploring new treatment paradigms in SCI results in data with more translational relevance to human SCI.

Aim: To investigate the safety and efficacy of intraspinal transplantation of directly reprogrammed neural precursor cells (drNPCs).

Methods: Seven non-human primates with verified complete thoracic SCI were divided into two groups: drNPC group (n = 4) was subjected to intraspinal transplantation of 5 million drNPCs rostral and caudal to the lesion site 2 wk post injury, and lesion control (n = 3) was injected identically with the equivalent volume of vehicle.

Results: Follow-up for 12 wk revealed that animals in the drNPC group demonstrated a significant recovery of the paralyzed hindlimb as well as recovery of somatosensory evoked potential and motor evoked potential of injured pathways. Magnetic resonance diffusion tensor imaging data confirmed the intraspinal transplantation of drNPCs did not adversely affect the morphology of the central nervous system or cerebrospinal fluid circulation. Subsequent immunohistochemical analysis showed that drNPCs maintained SOX2 expression characteristic of multipotency in the transplanted spinal cord for at least 12 wk, migrating to areas of axon growth cones.

Conclusion: Our data demonstrated that drNPC transplantation was safe and contributed to improvement of spinal cord function after acute SCI, based on neurological status assessment and neurophysiological recovery within 12 wk after transplantation. The functional improvement described was not associated with neuronal differentiation of the allogeneic drNPCs. Instead, directed drNPCs migration to the areas of active growth cone formation may provide exosome and paracrine trophic support, thereby further supporting the regeneration processes.

Keywords: Direct cell reprogramming; Directly reprogrammed neural precursor cells; Neural precursor cells; Nonhuman primates; Regenerative therapy, Evoked potentials; Spinal cord injury.