Subarachnoid transplantation of allogeneic human umbilical cord mesenchymal stem cells to treat late chronic spinal cord injury: protocol for a prospective, multicenter, open-label, single-arm clinical study

Abstract

Background: Spinal cord injury (SCI) is a devastating disease characterized by extensive cellular death, axonal disruption, and scar formation, leading to lifelong disability, muscle spasms, sensory deficits, and autonomic disturbances. Currently, no definitive therapy has been established to fundamentally improve the neurological deficits in late chronic SCI (disease duration >1 year), which is the most prevalent symptom among patients with SCI. Transplantation of human umbilical cord mesenchymal stem cells (hUC-MSCs) is a promising therapeutic alternative and pilot studies have demonstrated that hUC-MSCs can potentially improve neurological dysfunction with minimal adverse events (AEs). However, compared with the other phases of SCI, neurological dysfunction in late chronic SCI is more challenging to recover, as the severity of SCI tends to stabilize at 1 year after the initial injury. For these reasons, this clinical study aims to evaluate the safety and efficacy of subarachnoid transplantation of hUC-MSCs in patients with late chronic SCI.
Methods: This is a prospective, multicenter, open-label, single-arm clinical study involving 43 adult patients with late chronic SCI. Participants will receive four consecutive subarachnoid infusions of hUC-MSCs (1.0×106 cells/kg) and will be regularly followed up four times, scheduled at 1, 3, 6, and 12 months after the final hUC-MSC transplantation. Safety will be assessed on the basis of the incidence and severity of AEs and serious adverse events. Efficacy will be evaluated primarily by changes in the American Spinal Injury Association (ASIA) total score at 12 months after the final transplantation. The secondary end points include ASIA Impairment Scale, Spinal Cord Independence Measure-III, muscle spasms, bladder and bowel function, and neurophysiological assessments.
Discussion: Given the negligible spontaneous recovery characterizing late chronic SCI, this study employs a prospective single-arm design wherein participants serve as their own controls, thereby circumventing ethical constraints associated with placebo interventions. By evaluating repeated subarachnoid transplantation of human umbilical cord mesenchymal stem cells, this protocol aims to generate essential preliminary evidence regarding neural repair and immunomodulation, ultimately establishing a foundation for future large-scale randomized controlled trials in this refractory patient population.
Trial registration: ClinicalTrials.gov NCT03505034.

Keywords

Spinal cord injury / Human umbilical cord mesenchymal stem cells / Subarachnoid transplantation / Phase II study / Prospective research

CRediT authorship contribution statement

Mao Pang: Conceptualization, Methodology, Writing-original draft. Yang Yang: Conceptualization, Methodology, Writing-original draft. Jun Kang: Conceptualization, Methodology, Writing-original draft. Senyu Yao: Writing-review & editing. Xin Rong: Writingreview & editing. Kangkang Huang: Writing-review & editing. Hao Liu: Conceptualization, Methodology. Bin Liu: Conceptualization, Methodology. Limin Rong: Conceptualization, Methodology.

Ethics approval

The study ethics and study protocol have been approved by the Stem Cell Research Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University (2018-[03]) and the Ethics Committee on Stem Cell Clinical Research of West China Hospital of Sichuan University (2019-[02]), as well as by all relevant regulatory authorities. This clinical study will be performed in accordance with the principles of the World Medical Association Declaration of Helsinki, including all its amendments, and adheres to the standards of Good Clinical Practice. Once consensus on the results and conclusions of this clinical study has been reached, they will be submitted to the principal investigator and will be retained in paper form for at least 30 years. Even if the final results and conclusions do not meet the initial expectations, a manuscript describing this study will be prepared by the investigators at the sponsoring institution, in strict adherence to all standard operating procedures.

Consent for publication

Written informed consent approved by institutional ethics committees will be obtained from the patients before enrollment or any study-specific procedures. The parents who donated the umbilical cord signed the informed consent.

Data availability statement

Not applicable.

Funding

This work was supported by grants from the National Natural Science Foundation of China (U22A20297, 82172433, 82372400, 82072455, 82102642), the Key Research and Development Program of Guangzhou (202206060003), the Guangdong Basic and Applied Basic Research Foundation (2023A1515010313, 2024A1515013070, 2025A1515012371), and Guangzhou Science and Technology Project (2023A03J0203).

Declaration of competing interest

The authors declare that they have no conflicts of interest.

Acknowledgements

Not applicable.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.12464/j.issn.3079-7802.2025.003.

References

[1] Ahuja CS, Wilson JR, Nori S, et al. Traumatic spinal cord injury. Nat Rev Dis Primers. 2017; 3:17018. https://doi.org/10.1038/nrdp.2017.18.

[2] Hu X, Xu W, Ren Y, et al. Spinal cord injury: molecular mechanisms and therapeutic interventions. Sig Transduct Target Ther. 2023; 8:245. https://doi.org/10.1038/s41392-023-01477-6.

[3] Moraud EM, Capogrosso M, Formento E, et al. Mechanisms underlying the neuromodulation of spinal circuits for correcting gait and balance deficits after spinal cord injury. Neuron. 2016; 89:814-828. https://doi.org/10.1016/j.neuron.2016.01.009.

[4] Lima R, Monteiro A, Salgado AJ, Monteiro S, Silva NA. Pathophysiology and therapeutic approaches for spinal cord injury. Int J Mol Sci. 2022; 23:13833. https://doi.org/10.3390/ijms232213833.

[5] Guan B, Anderson DB, Chen L, Feng S, Zhou H. Global, regional and national burden of traumatic brain injury and spinal cord injury,1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. BMJ Open 2023; 13:e075049. https://doi.org/10.1136/bmjopen-2023-075049.

[6] Safdarian M, Trinka E, Rahimi-Movaghar V, et al. Global, regional, and national burden of spinal cord injury, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol 2023; 22:1026-1047. https://doi.org/10.1016/S1474-4422(23)00287-9.

[7] Wijker BJ, de Groot S, Boertje A-F, et al. Healthcare costs of pressure injuries among patients with a spinal cord injury within a Dutch rehabilitation center. Adv Skin Wound Care. 2025; 38:19-24. https://doi.org/10.1097/ASW.0000000000000259.

[8] Tian T, Zhang S, Yang M. Recent progress and challenges in the treatment of spinal cord injury. Protein Cell. 2023; 14:635-652. https://doi.org/10.1093/procel/pwad003.

[9] Weidner N, Abel R, Maier D, et al. Safety and efficacy of intrathecal antibodies to Nogo-A in patients with acute cervical spinal cord injury: a randomised, double-blind, multicentre, placebo-controlled, phase 2b trial. Lancet Neurol. 2025; 24:42-53. https://doi.org/10.1016/S1474-4422(24)00447-2.

[10] Hoang DM, Pham PT, Bach TQ, et al. Stem cell-based therapy for human diseases. Sig Transduct Target Ther. 2022; 7:272. https://doi.org/10.1038/s41392-022-01134-4.

[11] Zipser CM, Cragg JJ, Guest JD, et al. Cell-based and stem-cell-based treatments for spinal cord injury: evidence from clinical trials. Lancet Neurol. 2022; 21: 659-670. https://doi.org/10.1016/S1474-4422(21)00464-6.

[12] Liu Y, Zhao C, Zhang R, Pang Y, Li L, Feng S. Progression of mesenchymal stem cell regulation on imbalanced microenvironment after spinal cord injury. Stem Cell Res Ther. 2024; 15:343. https://doi.org/10.1186/s13287-024-03914-x.

[13] Zeng CW. Advancing spinal cord injury treatment through stem cell therapy: a comprehensive review of cell types, challenges, and emerging technologies in regenerative medicine. Int J Mol Sci. 2023; 24:14349. https://doi.org/10.3390/ijms241814349.

[14] Ribeiro BF, da Cruz BC, de Sousa BM, et al. Cell therapies for spinal cord injury: a review of the clinical trials and cell-type therapeutic potential. Brain. 2023; 146:2672-2693. https://doi.org/10.1093/brain/awad047.

[15] Xie Q, Liu R, Jiang J, et al. What is the impact of human umbilical cord mesenchymal stem cell transplantation on clinical treatment? Stem Cell Res Ther. 2020; 11:519. https://doi.org/10.1186/s13287-020-02011-z.

[16] Shen R, Lu Y, Cai C, et al. Research progress and prospects of benefit-risk assessment methods for umbilical cord mesenchymal stem cell transplantation in the clinical treatment of spinal cord injury. Stem Cell Res Ther. 2024; 15:196. https://doi.org/10.1186/s13287-024-03797-y.

[17] Galipeau J, Sensébé L. Mesenchymal stromal cells: clinical challenges and therapeutic opportunities. Cell Stem Cell. 2018; 22:824-833. https://doi.org/10.1016/j.stem.2018.05.004.

[18] Liu J, Han D, Wang Z, et al. Clinical analysis of the treatment of spinal cord injury with umbilical cord mesenchymal stem cells. Cytotherapy. 2013; 15:185-191.https://doi.org/10.1016/j.jcyt.2012.09.005.

[19] Albu S, Kumru H, Coll R, et al. Clinical effects of intrathecal administration of expanded Wharton jelly mesenchymal stromal cells in patients with chronic complete spinal cord injury: a randomized controlled study. Cytotherapy. 2021; 23:146-156. https://doi.org/10.1016/j.jcyt.2020.08.008.

[20] Awidi A, Al Shudifat A, El Adwan N, et al. Safety and potential efficacy of expanded mesenchymal stromal cells of bone marrow and umbilical cord origins in patients with chronic spinal cord injuries: a phase I/II study. Cytotherapy. 2024; 26:825-831. https://doi.org/10.1016/j.jcyt.2024.03.480.

[21] Yang Y, Pang M, Du C, et al. Repeated subarachnoid administrations of allogeneic human umbilical cord mesenchymal stem cells for spinal cord injury: a phase 1/ 2 pilot study. Cytotherapy. 2021; 23:57-64. https://doi.org/10.1016/j.jcyt.2020.09.012.

[22] Chen WC, Liu WF, Bai YY, et al. Transplantation of mesenchymal stem cells for spinal cord injury: a systematic review and network meta-analysis. J Transl Med. 2021; 19:178. https://doi.org/10.1186/s12967-021-02843-0.

[23] Dai G, Liu X, Zhang Z, et al. Comparative analysis of curative effect of CT-guided stem cell transplantation and open surgical transplantation for sequelae of spinal cord injury. J Transl Med. 2013; 11:315. https://doi.org/10.1186/1479-5876-11-315.

[24] Cheng H, Liu X, Hua R, et al. Clinical observation of umbilical cord mesenchymal stem cell transplantation in treatment for sequelae of thoracolumbar spinal cord injury. J Transl Med. 2014; 12:253. https://doi.org/10.1186/s12967-014-0253-7.

[25] Akhlaghpasand M, Tavanaei R, Hosseinpoor M, et al. Safety and potential effects of intrathecal injection of allogeneic human umbilical cord mesenchymal stem cell-derived exosomes in complete subacute spinal cord injury: a first-in-human, single-arm, open-label, phase I clinical trial. Stem Cell Res Ther. 2024; 15:264. https://doi.org/10.1186/s13287-024-03868-0.

[26] Cao TT, Chen H, Pang M, et al. Dose optimization of intrathecal administration of human umbilical cord mesenchymal stem cells for the treatment of subacute incomplete spinal cord injury. Neural Regen Res. 2022; 17:1785. https://doi.org/10.4103/1673-5374.332151.

[27] Liu G, Zhao Z, Wang H, et al. Therapeutic efficacy of human mesenchymal stem cells with different delivery route and dosages in rat models of spinal cord injury. Cell Transplant. 2022; 31:9636897221139734. https://doi.org/10.1177/09636897221139734.

[28] Lu Y, Zhang W, Tian Z, et al. The optimal transplantation strategy of umbilical cord mesenchymal stem cells in spinal cord injury: a systematic review and network meta-analysis based on animal studies. Stem Cell Res Ther. 2022; 13:441. https://doi.org/10.1186/s13287-022-03103-8.

[29] Chen C, Qiao X, Liu W, Fekete C, Reinhardt JD. Epidemiology of spinal cord injury in China: a systematic review of the Chinese and English literature. Spinal Cord. 2022; 60:1050-1061. https://doi.org/10.1038/s41393-022-00826-6.

[30] Yang Y, Pang M, Chen YY, et al. Human umbilical cord mesenchymal stem cells to treat spinal cord injury in the early chronic phase: study protocol for a prospective, multicenter, randomized, placebo-controlled, single-blinded clinical trial. Neural Regen Res. 2020; 15:1532-1538. https://doi.org/10.4103/1673-5374.274347.

[31] Chan AW, Tetzlaff JM, Gotzsche PC, et al.SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. Br Med J. 2013; 346:e7586. https://doi.org/10.1136/bmj.e7586.

[32] Chan AW, Tetzlaff JM, Altman DG, et al.SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med. 2013; 158:200. https://doi.org/10.7326/0003-4819-158-3-201302050-00583.

[33] Basch E, Reeve BB, Mitchell SA, et al. Development of the National Cancer Institute’s Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). J Natl Cancer Inst. 2014;106:dju244. https://doi.org/10.1093/jnci/dju244.

[34] Fawcett JW, Curt A, Steeves JD, et al. Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: spontaneous recovery after spinal cord injury and statistical power needed for therapeutic clinical trials. Spinal Cord. 2007; 45:190-205. https://doi.org/10.1038/sj.sc.3102007.

[35] Roberts TT, Leonard GR, Cepela DJ. Classifications in brief: American Spinal Injury Association (ASIA) Impairment Scale. Clin Orthop Relat Res. 2017; 475:1499-1504. https://doi.org/10.1007/s11999-016-5133-4.

[36] Kirshblum SC, Burns SP, Biering-Sorensen F, et al. International standards for neurological classification of spinal cord injury (Revised 2011). J Spinal Cord Med. 2011; 34:535-546. https://doi.org/10.1179/204577211X13207446293695.

[37] Kim RY, Thielen CC, Heydeman G, Mulcahey MJ. Standardized administration and scoring guidelines for the Spinal Cord Independence Measure Version 3.0 (SCIM-III). Spinal Cord. 2023; 61:296-306. https://doi.org/10.1038/s41393-023-00891-5.

[38] Round AM, Park SE, Walden K, Noonan VK, Townson AF, Krassioukov AV. An evaluation of the International Standards to Document Remaining Autonomic Function after Spinal Cord Injury: input from the international community. Spinal Cord. 2017; 55:198-203. https://doi.org/10.1038/sc.2016.152.

[39] Bohannon RW, Smith MB. Interrater reliability of a Modified Ashworth Scale of muscle spasticity. Phys Ther. 1987; 67:206-207. https://doi.org/10.1093/ptj/67.2.206.

[40] Penn RD, Savoy SM, Corcos D, et al. Intrathecal baclofen for severe spinal spasticity. N Engl J Med. 1989; 320:1517-1521. https://doi.org/10.1056/NEJM198906083202303.

[41] Geffner LF, Santacruz P, Izurieta M, et al. Administration of autologous bone marrow stem cells into spinal cord injury patients via multiple routes is safe and improves their quality of life: comprehensive case studies. Cell Transplant. 2008; 17:1277-1293. https://doi.org/10.3727/096368908787648074.

[42] Krogh K, Christensen P, Sabroe S, Laurberg S. Neurogenic bowel dysfunction score. Spinal Cord. 2006; 44:625-631. https://doi.org/10.1038/sj.sc.3101887.