Human neural stem cell transplantation (HuCNS-SC®) is a promising central nervous system (CNS) tissue repair strategy in patients with stable neurological deficits from chronic spinal cord injury (SCI). These immature human neural cells have been demonstrated to survive when transplanted in vivo, extend neural processes, form synaptic contacts, and improve functional outcomes after experimental SCI. A phase II single blind, randomized proof-of-concept study of the safety and efficacy of HuCNS-SC transplantation into the cervical spinal cord was undertaken in patients with chronic C5-7 tetraplegia, 4–24 months post-injury. In Cohort I (n = 6) dose escalation from 15,000,000 to 40,000,000 cells was performed to determine the optimum dose. In Cohort II an additional six participants were transplanted at target dose (40,000,000) and compared with four untreated controls. Within the transplant group, there were nine American Spinal Injury Association Impairment Scale (AIS) B and three AIS A participants with a median age at transplant of 28 years with an average time to transplant post-injury of 1 year. Immunosuppression was continued for 6 months post-transplant, and immunosuppressive blood levels of tacrolimus were achieved and well tolerated. At 1 year post-transplantation, there was no evidence of additional spinal cord damage, new lesions, or syrinx formation on magnetic resonance (MR) imaging. In summary, the incremental dose escalation design established surgical safety, tolerability, and feasibility in Cohort I. Interim analysis of Cohorts I and II demonstrated a trend toward Upper Extremity Motor Score (UEMS) and Graded Redefined Assessment of Strength, Sensibility, and Prehension (GRASSP) motor gains in the treated participants, but at a magnitude below the required clinical efficacy threshold set by the sponsor to support further development resulting in early study termination.
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References
1.
LeviA.D., GreenB.A., WangM.Y., DietrichW.D., BrindleT., VanniS., CasellaG., ElhammadyG., and JagidJ. (2009). Clinical application of modest hypothermia after spinal cord injury. J. Neurotrauma, 26, 407–415.
2.
LeviA.D., CasellaG., GreenB.A., DietrichW.D., VanniS., JagidJ., and WangM.Y. (2010). Clinical outcomes using modest intravascular hypothermia after acute cervical spinal cord injury. Neurosurgery, 66, 670–677.
3.
DididzeM., GreenB.A., DietrichW.D., VanniS., WangM.Y., and LeviA.D. (2013). Systemic hypothermia in acute cervical spinal cord injury: a case-controlled study. Spinal Cord, 51, 395–400.
4.
FehlingsM.G., KopjarB., and GrossmanR.G. (2016). 329 Efficacy and safety of riluzole in acute spinal cord injury: rationale and design of AOSpine Phase III Multicenter Double-Blinded Randomized Controlled Trial (RISCIS). Neurosurgery, 63, Suppl. 1, 196.
5.
CashaS., ZygunD., McGowanM.D., BainsI., YongV.W., and HurlbertR.J. (2012). Results of a phase II placebo-controlled randomized trial of minocycline in acute spinal cord injury. Brain, 135, 1224–1236.
6.
HallA., GieseN.A., and RichardsonW.D. (1996). Spinal cord oligodendrocytes develop from ventrally derived progenitor cells that express PDGF alpha-receptors. Development, 122, 4085–4094.
7.
HarperJ.M., KrishnanC., DarmanJ.S., DeshpandeD.M., PeckS., ShatsI., BackovicS., RothsteinJ.D., and KerrD.A. (2004). Axonal growth of embryonic stem cell–derived motoneurons in vitro and in motoneuron-injured adult rats. Proc. Natl. Acad. Sci. U. S. A. 101, 7123–7128.
8.
KerrC.L., LetzenB.S., HillC.M., AgrawalG., ThakorN.V., SterneckertJ.L., GearhartJ.D., and AllA.H. (2010). Efficient differentiation of human embryonic stem cells into oligodendrocyte progenitors for application in a rat contusion model of spinal cord injury. Int. J. Neurosci. 120, 305–313.
9.
MarquesS.A., AlmeidaF.M., FernandesA.M., dos Santos SouzaC., CadilheD.V., RehenS.K., and MartinezA.M. (2010). Predifferentiated embryonic stem cells promote functional recovery after spinal cord compressive injury. Brain Res. 1349, 115–128.
10.
NistorG.I., TotoiuM.O., HaqueN., CarpenterM.K., and KeirsteadH.S. (2005). Human embryonic stem cells differentiate into oligodendrocytes in high purity and myelinate after spinal cord transplantation. Glia, 49, 385–396.
11.
RossiS.L., NistorG., WyattT., YinH.Z., PooleA.J., WeissJ.H., GardenerM.J., DijkstraS., FischerD.F., and KeirsteadH.S. (2010). Histological and functional benefit following transplantation of motor neuron progenitors to the injured rat spinal cord. PloS One, 5, e11852.
12.
CummingsB.J., UchidaN., TamakiS.J., and AndersonA.J. (2006). Human neural stem cell differentiation following transplantation into spinal cord injured mice: association with recovery of locomotor function. Neurol. Res. 28, 474–481.
13.
CummingsB.J., UchidaN., TamakiS.J., SalazarD.L., HooshmandM., SummersR., GageF.H., and AndersonA.J. (2005). Human neural stem cells differentiate and promote locomotor recovery in spinal cord-injured mice. Proc. Natl. Acad. Sci. U. S. A. 102, 14, 069–14,074.
14.
ErcegS., RonaghiM., OriaM., RoselloM.G., AragoM.A., LopezM.G., RadojevicI., Moreno-ManzanoV., Rodriguez-JimenezF.J., BhattacharyaS.S., CordobaJ., and StojkovicM. (2010). Transplanted oligodendrocytes and motoneuron progenitors generated from human embryonic stem cells promote locomotor recovery after spinal cord transection. Stem Cells, 28, 1541–1549.
15.
WoodruffR.H., Tekki-KessarisN., StilesC.D., RowitchD.H., and RichardsonW.D. (2001). Oligodendrocyte development in the spinal cord and telencephalon: common themes and new perspectives. Int. J. Dev. Neurosci. 19, 379–385.
16.
SalazarD.L., UchidaN., HamersF.P., CummingsB.J., and AndersonA.J. (2010). Human neural stem cells differentiate and promote locomotor recovery in an early chronic spinal cord injury NOD-scid mouse model. PloS One, 5, e12272.
17.
SeldenN.R., Al-UzriA., HuhnS.L., KochT.K., SikoraD.M., Nguyen-DriverM.D., GuillaumeD.J., KohJ.L., GultekinS.H., AndersonJ.C., VogelH., SutcliffeT.L., JacobsY., and SteinerR.D. (2013). Central nervous system stem cell transplantation for children with neuronal ceroid lipofuscinosis. J. Neurosurg. Pediatr. 11, 643–652.
18.
GuptaN., HenryR.G., StroberJ., KangS.M., LimD.A., BucciM., CaverzasiE., GaetanoL., MandelliM.L., RyanT., PerryR., FarrellJ., JeremyR.J., UlmanM., HuhnS.L., BarkovichA.J., and RowitchD.H. (2012). Neural stem cell engraftment and myelination in the human brain. Sci. Transl. Med., 4, 155ra137.
19.
PilttiK.M., SalazarD.L., UchidaN., CummingsB.J., and AndersonA.J. (2013). Safety of human neural stem cell transplantation in chronic spinal cord injury. Stem Cells Transl. Med. 2, 961–974.
20.
GlassJ.D., HertzbergV.S., BoulisN.M., RileyJ., FedericiT., PolakM., BordeauJ., FournierC., JoheK., HazelT., CudkowiczM., AtassiN., BorgesL.F., RutkoveS.B., DuellJ., PatilP.G., GoutmanS.A., and FeldmanE.L. (2016). Transplantation of spinal cord-derived neural stem cells for ALS: analysis of phase 1 and 2 trials. Neurology, 87, 392–400.
21.
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.
22.
LeviA.D., OkonkwoD.O., ParkP., JenkinsA.L.3rd, KurpadS.N., ParrA.M., GanjuA., AarabiB., KimD., CashaS., FehlingsM.G., HarropJ.S., AndersonK.D., GageA., HsiehJ., HuhnS., CurtA., and GuzmanR. (2017). Emerging safety of intramedullary transplantation of human neural stem cells in chronic cervical and thoracic spinal cord injury. Neurosurgery. 82, 562–575.
23.
FedericiT., HurtigC.V., BurksK.L., RileyJ.P., KrishnaV., MillerB.A., SribnickE.A., MillerJ.H., GrinN., LamannaJ.J., and BoulisN.M. (2012). Surgical technique for spinal cord delivery of therapies: demonstration of procedure in gottingen minipigs. J. Vis. Exp. 70, e4371.
24.
LamannaJ.J., MillerJ.H., RileyJ.P., HurtigC.V., and BoulisN.M. (2013). Cellular therapeutics delivery to the spinal cord: technical considerations for clinical application. Ther. Deliv. 4, 1397–1410.
25.
RaoreB., FedericiT., TaubJ., WuM.C., RileyJ., FranzC.K., KliemM.A., SnyderB., FeldmanE.L., JoheK., and BoulisN.M. (2011). Cervical multilevel intraspinal stem cell therapy: assessment of surgical risks in Gottingen minipigs. Spine, 36, E164–171.
26.
RileyJ., FedericiT., ParkJ., SuzukiM., FranzC.K., TorkC., McHughJ., TengQ., SvendsenC., and BoulisN.M. (2009). Cervical spinal cord therapeutics delivery: preclinical safety validation of a stabilized microinjection platform. Neurosurgery, 65, 754–761.
27.
LeviA.D., TatorC.H., and BungeR.P. (1996). Clinical syndromes associated with disproportionate weakness of the upper versus the lower extremities after cervical spinal cord injury. Neurosurgery, 38, 179–183.
28.
AndersonK.D., GuestJ.D., DietrichW.D., Bartlett BungeM., CurielR., DididzeM., GreenB.A., KhanA., PearseD.D., Saraf-LaviE., Widerstrom-NogaE., WoodP., and LeviA.D. (2017). Safety of autologous human schwann cell transplantation in subacute thoracic spinal cord injury. J. Neurotrauma, 34, 2950–2963.
29.
SteevesJ.D., KramerJ.K., FawcettJ.W., CraggJ., LammertseD.P., BlightA.R., MarinoR.J., DitunnoJ.F.Jr., ColemanW.P., GeislerF.H., GuestJ., JonesL., BurnsS., SchubertM., van HedelH.J., CurtA., and GroupE.S. (2011). Extent of spontaneous motor recovery after traumatic cervical sensorimotor complete spinal cord injury. Spinal Cord, 49, 257–265.
30.
GhobrialG.M., AndersonK.D., DididzeM., Martinez–BarrizonteJ., SunnG.H., GantK.L., and LeviA.D. (2017). Human neural stem cell transplantation in chronic cervical spinal cord injury: functional outcomes at 12 months in a phase II clinical trial. Neurosurgery, 64, 87–91.
31.
AndersonA.J., PilittiK.M., HooshmandM.J., NishiR.A., and CummingsB.J. (2017). Preclinical efficacy failure of human CNS-derived stem cells for use in the pathway study of cervical spinal cord injury. Stem Cell Reports, 8, 249–263.
32.
MarshS.E., YeungS.T., TorresM., LauL., DavisJ.L., MonukiE.S., PoonW.W., and Blurton-JonesM. (2017). HuCNS–SC human NSCs fail to differentiate, form ectopic clusters, and provide no cognitive benefits in a transgenic model of Alzheimer's disease. Stem Cell Reports, 8, 235–248.
33.
MonukiE.S., AndersonA.J., Blurton-JonesM. and CummingsB.J. (2017). Response to StemCells Inc. Stem Cell Reports, 8, 195–197.
34.
StemCells Inc. Former Management (2017). Reaction from StemCells, Inc. to Two Papers in Stem Cell Reports on the Efficacy of Human NSCs in Mouse Models of Alzheimer's Disease and Spinal Cord Injury. Stem Cell Reports, 8, 194–195.
35.
TempleS., and StuderL. (2017). Lessons Learned from Pioneering Neural Stem Cell Studies. Stem Cell Reports, 8, 191–193.
36.
JaeschkeR., SingerJ., and GuyattG.H. (1989). Measurement of health status. Ascertaining the minimal clinically important difference. Control Clin. Trials, 10, 407–415.
37.
PaulA.R., KumarV., RothS., GoochM.R., and PilitsisJ.G. (2017). Establishing minimal clinically important difference of spinal cord stimulation therapy in post–laminectomy syndrome. Neurosurgery, 81, 1011–1015.
38.
WuX., LiuJ., TanadiniL.G., LammertseD.P., BlightA.R., KramerJ.L., ScivolettoG., JonesL., KirshblumS., AbelR., FawcettJ., Field–FoteE., GuestJ., LevinsonB., MaierD., TanseyK., WeidnerN., TetzlaffW.G., HothornT., CurtA., and SteevesJ.D. (2015). Challenges for defining minimal clinically important difference (MCID) after spinal cord injury. Spinal Cord, 53, 84–91.
39.
BohlmanH.H. and AndersonP.A. (1992). Anterior decompression and arthrodesis of the cervical spine: long–term motor improvement. Part I—Improvement in incomplete traumatic quadriparesis. J. Bone Joint Surg. Am. 74, 671–682.
40.
BohlmanH.H., KirkpatrickJ.S., DelamarterR.B. and LeventhalM. (1994). Anterior decompression for late pain and paralysis after fractures of the thoracolumbar spine. Clin. Orthop. Relat. Res., 300, 24–29.
41.
AndersonP.A. and BohlmanH.H. (1992). Anterior decompression and arthrodesis of the cervical spine: long–term motor improvement. Part II—Improvement in complete traumatic quadriplegia. J Bone Joint Surg Am, 74, 683–692.
42.
MackinnonS.E., YeeA., and RayW.Z. (2012). Nerve transfers for the restoration of hand function after spinal cord injury. J. Neurosurg. 117, 176–185.
43.
Kalsi–RyanS., BeatonD., AhnH., AskesH., DrewB., CurtA., PopovicM.R., WangJ., VerrierM.C., and FehlingsM.G. (2016). Responsiveness, sensitivity, and minimally detectable difference of the Graded and Redefined Assessment of Strength, Sensibility, and Prehension, Version 1.0. J. Neurotrauma, 33, 307–314.
44.
VelstraI.M., CurtA., FrotzlerA., AbelR., Kalsi–RyanS., RietmanJ.S., and BolligerM. (2015). Changes in strength, sensation, and prehension in acute cervical spinal cord injury: European Multicenter Responsiveness Study of the GRASSP. Neurorehabil. Neural Repair, 29, 755–766.
45.
ZariffaJ., CurtA., VerrierM.C., FehlingsM.G., and Kalsi–RyanS., (2016). Predicting task performance from upper extremity impairment measures after cervical spinal cord injury. Spinal Cord, 54, 1145–1151.
46.
Kalsi–RyanS., BeatonD., CurtA., DuffS., PopovicM.R., RudheC., FehlingsM.G., and VerrierM.C. (2012). The Graded Redefined Assessment of Strength Sensibility and Prehension: reliability and validity. J. Neurotrauma, 29, 905–914.
47.
Kalsi-RyanS., CurtA., VerrierM.C., and FehlingsM.G. (2012). Development of the Graded Redefined Assessment of Strength, Sensibility and Prehension (GRASSP): reviewing measurement specific to the upper limb in tetraplegia. J. Neurosurg. Spine, 17, 65–76.
48.
CurtA., LeviA.D., and SchwabJ.M. (2017). Challenges to translation and the hippocratic oath by premature termination of spinal cord stem cell–based trials. JAMA Neurol. 74, 635–636.
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