A phase 1 open-label, non-randomized clinical trial was conducted to determine feasibility and safety of autologous human Schwann cell (ahSC) transplantation accompanied by rehabilitation in participants with chronic spinal cord injury (SCI). Magnetic resonance imaging (MRI) was used to screen eligible participants to estimate an individualized volume of cell suspension to be implanted. The trial incorporated standardized multi-modal rehabilitation before and after cell delivery. Participants underwent sural nerve harvest, and ahSCs were isolated and propagated in culture. The dose of culture-expanded ahSCs injected into the chronic spinal cord lesion of each individual followed a cavity-filling volume approach. Primary outcome measures for safety and trend-toward efficacy were assessed. Two participants with American Spinal Injury Association Impairment Scale (AIS) A and two participants with incomplete chronic SCI (AIS B, C) were each enrolled in cervical and thoracic SCI cohorts (n = 8 total). All participants completed the study per protocol, and no serious adverse events related to sural nerve harvest or ahSC transplantation were reported. Urinary tract infections and skin abrasions were the most common adverse events reported. One participant experienced a 4-point improvement in motor function, a 6-point improvement in sensory function, and a 1-level improvement in neurological level of injury. Follow-up MRI in the cervical (6 months) and thoracic (24 months) cohorts revealed a reduction in cyst volume after transplantation with reduced effect over time. This phase 1 trial demonstrated the feasibility and safety of ahSC transplantation combined with a multi-modal rehabilitation protocol for participants with chronic SCI.
Get full access to this article
View all access options for this article.
References
1.
BungeR.P., PuckettW.R., BecerraJ.L., MarcilloA., and QuencerR.M. (1993). Observations on the pathology of human spinal cord injury. A review and classification of 22 new cases with details from a case of chronic cord compression with extensive focal demyelination. Adv. Neurol. 59, 75–89.
2.
Cohen-AdadJ., El MendiliM.-M., LehéricyS., PradatP.F., BlanchoS., RossignolS., and BenaliH. (2011). Demyelination and degeneration in the injured human spinal cord detected with diffusion and magnetization transfer MRI. NeuroImage, 55, 1024–1033.
3.
GuestJ.D., HiesterE.D., and BungeR.P. (2005). Demyelination and Schwann cell responses adjacent to injury epicenter cavities following chronic human spinal cord injury. Exp. Neurol. 192, 384–393.
4.
NorenbergM.D., SmithJ., and MarcilloA. (2004). The pathology of human spinal cord injury: defining the problems. J. Neurotrauma, 21, 429–440.
5.
WolfeD.L., HayesK.C., HsiehJ.T., and PotterP.J. (2001). Effects of 4-aminopyridine on motor evoked potentials in patients with spinal cord injury: a double-blinded, placebo-controlled crossover trial. J. Neurotrauma, 18, 757–771.
6.
BruceJ.H., NorenbergM.D., KraydiehS., PuckettW., MarcilloA., and DietrichD. (2000). Schwannosis: role of gliosis and proteoglycan in human spinal cord injury. J. Neurotrauma, 17, 781–788.
7.
BarakatD.J., GaglaniS.M., NeravetlaS.R., SanchezA.R., AndradeC.M., PressmanY., PuzisR., GargM.S., BungeM.B., and PearseD.D. (2005). Survival, integration, and axon growth support of glia transplanted into the chronically contused spinal cord. Cell Transplant. 14, 225–240.
8.
GuestJ., SantamariaA.J., and BenavidesF.D. (2013). Clinical translation of autologous Schwann cell transplantation for the treatment of spinal cord injury. Curr. Opin. Organ Transplant. 18, 682–689.
9.
TakamiT., OudegaM., BatesM.L., WoodP.M., KleitmanN., and BungeM.B. (2002). Schwann cell but not olfactory ensheathing glia transplants improve hindlimb locomotor performance in the moderately contused adult rat thoracic spinal cord. J. Neurosci. 22, 6670–6681.
10.
XuX.M., ChenA., GuénardV., KleitmanN., and BungeM.B. (1997). Bridging Schwann cell transplants promote axonal regeneration from both the rostral and caudal stumps of transected adult rat spinal cord. J. Neurocytol. 26, 1–16.
11.
PearseD.D., SanchezA.R., PereiraF.C., AndradeC.M., PuzisR., PressmanY., GoldenK., KitayB.M., BlitsB., WoodP.M., and BungeM.B. (2007). Transplantation of Schwann cells and/or olfactory ensheathing glia into the contused spinal cord: Survival, migration, axon association, and functional recovery. Glia, 55, 976–1000.
12.
PearseD.D., MarcilloA.E., OudegaM., LynchM.P., WoodP.M., and BungeM.B. (2004). Transplantation of Schwann cells and olfactory ensheathing glia after spinal cord injury: does pretreatment with methylprednisolone and interleukin-10 enhance recovery?. J. Neurotrauma, 21, 1223–1239.
13.
SchaalS.M., KitayB.M., ChoK.S., LoT.P., BarakatD.J., MarcilloA.E., SanchezA.R., AndradeC.M., and PearseD.D. (2007). Schwann cell transplantation improves reticulospinal axon growth and forelimb strength after severe cervical spinal cord contusion. Cell Transplant. 16, 207–228.
14.
PearseD.D., PereiraF.C., MarcilloA.E., BatesM.L., BerrocalY.A., FilbinM.T., and BungeM.B. (2004). cAMP and Schwann cells promote axonal growth and functional recovery after spinal cord injury. Nat. Med. 10, 610–616.
15.
TaylorJ.S.H., and BamptonE.T.W. (2004). Factors secreted by Schwann cells stimulate the regeneration of neonatal retinal ganglion cells. J. Anat. 204, 25–31.
16.
ToyotaB., CarbonettoS., and DavidS. (1990). A dual laminin/collagen receptor acts in peripheral nerve regeneration. Proc. Natl. Acad. Sci. U. S. A. 87, 1319–1322.
17.
MartiniR. and SchachnerM. (1988). Immunoelectron microscopic localization of neural cell adhesion molecules (L1, N-CAM, and myelin-associated glycoprotein) in regenerating adult mouse sciatic nerve. J. Cell. Biol. 106, 1735–1746.
18.
BamberN.I., LiH., LuX., OudegaM., AebischerP., and XuX.M. (2001). Neurotrophins BDNF and NT-3 promote axonal re-entry into the distal host spinal cord through Schwann cell-seeded mini-channels. Eur. J. Neurosci. 13, 257–268.
19.
GuestJ.D., RaoA., OlsonL., BungeM.B., and BungeR.P. (1997). The ability of human Schwann cell grafts to promote regeneration in the transected nude rat spinal cord. Exp. Neurol. 148, 502–522.
20.
XuX.M., GuénardV., KleitmanN., and BungeM.B. (1995). Axonal regeneration into Schwann cell-seeded guidance channels grafted into transected adult rat spinal cord. J. Comp. Neurol. 351, 145–160.
21.
XuX.M., ZhangS.X., LiH., AebischerP., and BungeM.B. (1999). Regrowth of axons into the distal spinal cord through a Schwann-cell-seeded mini-channel implanted into hemisected adult rat spinal cord. Eur. J. Neurosci. 11, 1723–1740.
22.
ImaizumiT., LankfordK.L., and KocsisJ.D. (2000). Transplantation of olfactory ensheathing cells or Schwann cells restores rapid and secure conduction across the transected spinal cord. Brain Res, 854, 70–78.
23.
PinzonA., CalancieB., OudegaM., and NogaB.R. (2001). Conduction of impulses by axons regenerated in a Schwann cell graft in the transected adult rat thoracic spinal cord. J. Neurosci. Res. 64, 533–541.
24.
BastidasJ., AthaudaG., De La CruzG., ChanW.-M., GolshaniR., BerrocalY., HenaoM., LalwaniA., MannojiC., AssiM., OteroP.A., KhanA., MarcilloA.E., NorenbergM., LeviA.D., WoodP.M., GuestJ.D., DietrichW.D., Bartlett BungeM., and PearseD.D. (2017). Human Schwann cells exhibit long-term cell survival, are not tumorigenic and promote repair when transplanted into the contused spinal cord. Glia, 65, 1278–1301.
25.
PearseD.D., BastidasJ., IzabelS.S., and GhoshM. (2018). Schwann cell transplantation subdues the pro-inflammatory innate immune cell response after spinal cord injury. Int. J. Mol. Sci. 19.
26.
AndersonK.D., GuestJ.D., DietrichW.D., Bartlett BungeM., CurielR., DididzeM., GreenB.A., KhanA., PearseD.D., Saraf-LaviE., Widerström-NogaE., WoodP., and LeviA.D. (2017). Safety of autologous human Schwann cell transplantation in subacute thoracic spinal cord injury. J. Neurotrauma, 34, 2950–2963.
27.
SantamariaA.J., BenavidesF.D., SaraivaP.M., AndersonK.D., KhanA., LeviA.D., DietrichW.D., and GuestJ.D. (2020). Neurophysiological changes in the first year after cell transplantation in sub-acute complete paraplegia. Front. Neurol. 11, 514181.
28.
ThuretS., MoonL.D.F., and GageF.H. (2006). Therapeutic interventions after spinal cord injury. Nat. Rev. Neurosci. 7, 628–643.
29.
FouadK. and TetzlaffW. (2012). Rehabilitative training and plasticity following spinal cord injury. Exp. Neurol. 235, 91–99.
30.
van HedelH.J.A. and DietzV. (2010). Rehabilitation of locomotion after spinal cord injury. Restor. Neurol. Neurosci. 28, 123–134.
31.
AngeliC.A., BoakyeM., MortonR.A., VogtJ., BentonK., ChenY., FerreiraC.K., and HarkemaS.J. (2018). Recovery of over-ground walking after chronic motor complete spinal cord injury. N. Engl. J. Med. 379, 1244–1250.
32.
GadP., LeeS., TerrafrancaN., ZhongH., TurnerA., GerasimenkoY., and EdgertonV.R. (2018). Non-invasive activation of cervical spinal networks after severe paralysis. J. Neurotrauma, 35, 2145–2158.
33.
WagnerF.B., MignardotJ.B., Le Goff-MignardotC.G., DemesmaekerR., KomiS., CapogrossoM., RowaldA., SeáñezI., CabanM., PirondiniE., VatM., McCrackenL.A., HeimgartnerR., FodorI., WatrinA., SeguinP., PaolesE., Van Den KeybusK., EberleG., SchurchB., PralongE., BecceF., PriorJ., BuseN., BuschmanR., NeufeldE., KusterN., CardaS., von ZitzewitzJ., DelattreV., DenisonT., LambertH., MinassianK., BlochJ., and CourtineG. (2018). Targeted neurotechnology restores walking in humans with spinal cord injury. Nature, 563, 65–71.
34.
JoH.J. and PerezM.A. (2020). Corticospinal-motor neuronal plasticity promotes exercise-mediated recovery in humans with spinal cord injury. Brain, 143, 1368–1382.
35.
Gomes-OsmanJ., CortesM., GuestJ., and Pascual-LeoneA. (2016). A systematic review of experimental strategies aimed at improving motor function after acute and chronic spinal cord iInjury. J. Neurotrauma, 33, 425–438.
36.
MorrisonS.A., LorenzD., EskayC.P., ForrestG.F., and BassoD.M. (2018). Longitudinal recovery and reduced costs after 120 sessions of locomotor training for motor incomplete spinal cord injury. Arch. Phys. Med. Rehabil. 99, 555–562.
37.
GantK.L., NagleK.G., CowanR.E., Field-FoteE.C., NashM.S., KresslerJ., ThomasC.K., CastellanosM., Widerström-NogaE., and AndersonK.D. (2018). Body system effects of a multi-modal training program targeting chronic, motor complete thoracic spinal cord injury. J. Neurotrauma, 35, 411–423.
38.
MaherJ.L., AndersonK.D., GantK.L., and CowanR.E. (2021). Development and deployment of an at-home strength and conditioning program to support a phase I trial in persons with chronic spinal cord injury. Spinal Cord, 59, 44–54
39.
HendersonG.E., ChurchillL.R., DavisA.M., EasterM.M., GradyC., JoffeS., KassN., KingN.M.P., LidzC.W., MillerF.G., NelsonD.K., PeppercornJ., RothschildB.B., SankarP., WilfondB.S., and ZimmerC.R. (2007). Clinical trials and medical care: defining the therapeutic misconception. PLoS Med. 4, e324.
40.
Widerström-NogaE., Biering-SørensenF., BryceT., CardenasD.D., FinnerupN.B., JensenM.P., RichardsJ.S., and SiddallP.J. (2008). The international spinal cord injury pain basic data set. Spinal Cord, 46, 818–823.
41.
WongM.L., FlemingL., RobayoL.E., and Widerström-NogaE. (2020). Utility of the Neuropathic Pain Symptom Inventory in people with spinal cord injury. Spinal Cord, 58, 35–42.
42.
WongM.L., TibbettJ., AdedolapoT., and Widerstrom-NogaE. (2019). The Graph-DCK Scale: a measure of dorsal column function after spinal cord injury. Spinal Cord, 57, 412–418.
43.
BenzE.N., HornbyT.G., BodeR.K., ScheidtR.A., and SchmitB.D. (2005). A physiologically based clinical measure for spastic reflexes in spinal cord injury. Arch. Phys. Med. Rehabil. 86, 52–59.
44.
ThompsonC.K. and HornbyT.G. (2013). Divergent modulation of clinical measures of volitional and reflexive motor behaviors following serotonergic medications in human incomplete spinal cord injury. J. Neurotrauma, 30, 498–502.
45.
AkpinarP., AticiA., OzkanF.U., AktasI., KulcuD.G., SarıA., and DurmusB. (2017). Reliability of the Modified Ashworth Scale and Modified Tardieu Scale in patients with spinal cord injuries. Spinal Cord, 55, 944–949.
46.
NessL.L. and Field-FoteE.C. (2009). Effect of whole-body vibration on quadriceps spasticity in individuals with spastic hypertonia due to spinal cord injury. Restor. Neurol. Neurosci. 27, 621–631.
47.
KirshblumS.C., WaringW., and Biering-SorensenF. (2011). Reference for the 2011 revision of the International Standards for Neurological Classification of Spinal Cord Injury. J Spinal Cord Med, 34, 547–554.
48.
ItzkovichM., GelernterI., and Biering-SorensenF. (2007). The Spinal Cord Independence Measure (SCIM) version III: reliability and validity in a multi-center international study. Disabil. Rehabil. 29, 1926–1933.
49.
ScivolettoG., TamburellaF., LaurenzaL., and MolinariM. (2013). The spinal cord independence measure: how much change is clinically significant for spinal cord injury subjects. Disabil. Rehabil. 35, 1808–1813.
50.
CharlifueS., PostM.W., Biering-SørensenF., CatzA., DijkersM., GeyhS., HorsewellJ., NoonanV., NoreauL., TateD., and SinnottK.A. (2012). International spinal cord injury quality of life basic data set. Spinal Cord, 50, 672–675.
51.
TulskyD.S., KisalaP.A., VictorsonD., TateD.G., HeinemannA.W., CharlifueS., KirshblumS.C., FyffeD., GershonR., SpungenA.M., BombardierC.H., Dyson-HudsonT.A., AmtmannD., KalpakjianC.Z., ChoiS.W., JetteA.M., ForchheimerM., and CellaD. (2015). Overview of the Spinal Cord Injury–Quality of Life (SCI-QOL) measurement system. J. Spinal Cord Med. 38, 257–269.
52.
Biering-SorensenF., CraggsM., and KennellyM. (2008). International lower urinary tract function basic spinal cord injury data set. Spinal Cord, 46, 325–330.
53.
KroghK., PerkashI., StiensS.A., and Biering-SørensenF. (2009). International bowel function basic spinal cord injury data set. Spinal Cord, 47, 230–234.
54.
GravesD.E., FrankiewiczR.G., and DonovanW.H. (2006). Construct validity and dimensional structure of the ASIA motor scale. J. Spinal Cord Med. 29, 39–45.
55.
MarinoR.J., JonesL., KirshblumS., TalJ., and DasguptaA. (2008). Reliability and repeatability of the motor and sensory examination of the international standards for neurological classification of spinal cord injury. J. Spinal Cord Med. 31, 166–170.
56.
NashM.S., van de VenI., van ElkN., and JohnsonB.M. (2007). Effects of circuit resistance training on fitness attributes and upper-extremity pain in middle-aged men with paraplegia. Arch. Phys. Med. Rehabil. 88, 70–75.
57.
BurksJ.D., GantK.L., GuestJ.D., JamshidiA.G., CoxE.M., AndersonK.D., DietrichW.D., BungeM.B., GreenB.A., KhanA., PearseD.D., Saraf-LaviE., and LeviA.D. (2019). Imaging characteristics of chronic spinal cord injury identified during screening for a cell transplantation clinical trial. Neurosurg. Focus, 46, E8.
58.
CasasC.E., HerreraL.P., PrusmackC., RuenesG., MarcilloA., and GuestJ.D. (2005). Effects of epidural hypothermic saline infusion on locomotor outcome and tissue preservation after moderate thoracic spinal cord contusion in rats. J. Neurosurg. Spine, 2, 308–318.
59.
DuerstockB.S. and BorgensR.B. (2002). Three-dimensional morphometry of spinal cord injury following polyethylene glycol treatment. J. Exp. Biol. 205, 13–24.
60.
NishiR.A., LiuH., ChuY., HamamuraM., SuM.Y., NalciogluO., and AndersonA.J. (2007). Behavioral, histological, and ex vivo magnetic resonance imaging assessment of graded contusion spinal cord injury in mice. J. Neurotrauma, 24, 674–689.
61.
FreundM., HabichtD., AschoffA., KalvineK., and SartorK. (2002). Posttraumatic syringomyelia: volumetric phantom and patient studies using MR imaging. Eur. Radiol. 12, 2965–2972.
62.
NideckerA., KocherM., MaederM., GratzlO., ZächG.A., BenzU.F., and BurckhardtB. (1991). MR-imaging of chronic spinal cord injury. Association with neurologic function. Neurosurg. Rev. 14, 169–179.
63.
GuestJ., BenavidesF., PadgettK., MendezE., and TovarD. (2011). Technical aspects of spinal cord injections for cell transplantation. Clinical and translational considerations. Brain Res. Bull. 84, 267–279.
64.
SantamaríaA.J., SolanoJ.P., BenavidesF.D., and GuestJ.D. (2018). Intraspinal delivery of Schwann cells for spinal cord injury. Methods Mol. Biol. 1739, 467–484.
65.
LeviA.D., AndersonK.D., OkonkwoD.O., ParkP., BryceT.N., KurpadS.N., AarabiB., HsiehJ., and GantK. (2019). Clinical outcomes from a multi-center study of human neural stem cell transplantation in chronic cervical spinal cord injury. J. Neurotrauma, 36, 891–902.
66.
BungeR.P., PuckettW.R., and HiesterE.D. (1997). Observations on the pathology of several types of human spinal cord injury, with emphasis on the astrocyte response to penetrating injuries. Adv. Neurol. 72, 305–315.
67.
KakulasB.A. (1999). The applied neuropathology of human spinal cord injury. Spinal Cord, 37, 79–88.
68.
BungeR.P. (1993). Expanding roles for the Schwann cell: ensheathment, myelination, trophism and regeneration. Curr. Opin. Neurobiol. 3, 805–809.
69.
SasakiM. and IdeC. (1991). Aberrant remyelination of axons after heat injury in the dorsal funiculus of rat spinal cord. Acta Neuropathol. (Berl.) 81, 557–561.
70.
GuestJ.D., HesseD., SchnellL., SchwabM.E., BungeM.B., and BungeR.P. (1997). Influence of IN-1 antibody and acidic FGF-fibrin glue on the response of injured corticospinal tract axons to human Schwann cell grafts. J. Neurosci. Res. 50, 888–905.
71.
KeirsteadH.S., MorganS.V., WilbyM.J., and FawcettJ.W. (1999). Enhanced axonal regeneration following combined demyelination plus schwann cell transplantation therapy in the injured adult spinal cord. Exp. Neurol. 159, 225–236.
72.
TuszynskiM.H., WeidnerN., McCormackM., MillerI., PowellH., and ConnerJ. (1998). Grafts of genetically modified Schwann cells to the spinal cord: survival, axon growth, and myelination. Cell Transplant. 7, 187–196.
73.
WeidnerN., BleschA., GrillR.J., and TuszynskiM.H. (1999). Nerve growth factor-hypersecreting Schwann cell grafts augment and guide spinal cord axonal growth and remyelinate central nervous system axons in a phenotypically appropriate manner that correlates with expression of L1. J. Comp. Neurol. 413, 495–506.
74.
LaPorteR.E., AdamsL.L., SavageD.D., BrenesG., DearwaterS., and CookT. (1984). The spectrum of physical activity, cardiovascular disease and health: an epidemiologic perspective. Am. J. Epidemiol. 120, 507–517.
75.
NashM.S. and GaterD.R. (2020). Cardiometabolic disease and dysfunction following spinal cord injury: origins and guideline-based countermeasures. Phys. Med. Rehabil. Clin. N. Am. 31, 415–436.
76.
LoyK. and BareyreF.M. (2019). Rehabilitation following spinal cord injury: how animal models can help our understanding of exercise-induced neuroplasticity. Neural Regen. Res. 14, 405–412.
77.
SteevesJ.D., LammertseD.P., KramerJ.L.K., KleitmanN., Kalsi-RyanS., JonesL., CurtA., BlightA.R., and AndersonK.D. (2012). Outcome measures for acute/subacute cervical sensorimotor complete (AIS-A) spinal cord injury during a phase 2 clinical trial. Top. Spinal Cord Inj. Rehabil. 18, 1–14.
78.
TuszynskiM.H., SteevesJ.D., FawcettJ.W., LammertseD., KalichmanM., RaskC., CurtA., DitunnoJ.F., FehlingsM.G., GuestJ.D., EllawayP.H., KleitmanN., BartlettP.F., BlightA.R., DietzV., DobkinB.H., GrossmanR., andPrivatA., ; International Campaign for Cures of Spinal Cord InjuryParalysis. (2007). Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP Panel: clinical trial inclusion/exclusion criteria and ethics. Spinal Cord, 45, 222–231.
79.
CastroM.J., AppleD.F., HillegassE.A., and DudleyG.A. (1999). Influence of complete spinal cord injury on skeletal muscle cross-sectional area within the first 6 months of injury. Eur. J. Appl. Physiol. 80, 373–378.
80.
SpungenA.M., AdkinsR.H., StewartC.A., WangJ., PiersonR.N., WatersR.L., and BaumanW.A. (2003). Factors influencing body composition in persons with spinal cord injury: a cross-sectional study. J. Appl. Physiol. 95, 2398–2407.
81.
NashM.S., BilskerS., MarcilloA.E., IsaacS.M., BotelhoL.A., KloseK.J., GreenB.A., RountreeM.T., and SheaJ.D. (1991). Reversal of adaptive left ventricular atrophy following electrically-stimulated exercise training in human tetraplegics. Paraplegia, 29, 590–599.
82.
RagnarssonK.T., PollackS., O'DanielW., EdgarR., PetrofskyJ., and NashM.S. (1988). Clinical evaluation of computerized functional electrical stimulation after spinal cord injury: a multicenter pilot study. Arch. Phys. Med. Rehabil. 69, 672–677.
83.
BartusK., GalinoJ., JamesN.D., Hernandez-MirandaL.R., DawesJ.M., FrickerF.R., GarrattA.N., McMahonS.B., RamerM.S., BirchmeierC., BennettD.L.H., and BradburyE.J. (2016). Neuregulin-1 controls an endogenous repair mechanism after spinal cord injury. Brain J. Neurol. 139, 1394–1416.
84.
WarrenP.M., AndrewsM.R., SmithM., BartusK., BradburyE.J., VerhaagenJ., FawcettJ.W., and KwokJ.C.F. (2020). Secretion of a mammalian chondroitinase ABC aids glial integration at PNS/CNS boundaries. Sci. Rep. 10, 11262.
85.
BungeM.B. (2016). Efficacy of Schwann cell transplantation for spinal cord repair is improved with combinatorial strategies. J. Physiol. 594, 3533–3538.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
