Clinical Trials of Stem Cell Treatment for Spinal Cord Injury

There are more than one million patients worldwide suffering paralysis caused by spinal cord injury (SCI). SCI causes severe socioeconomic problems not only to the patients and their caregivers but also to society; therefore, the development of innovative treatments is crucial. Many pharmacological therapies have been attempted in an effort to reduce SCI-related damage; however, no single therapy that could dramatically improve the serious long-term sequelae of SCI has emerged. Stem cell transplantation therapy, which can ameliorate damage or regenerate neurological networks, has been proposed as a promising candidate for SCI treatment, and many basic and clinical experiments using stem cells for SCI treatment have been launched, with promising results. However, the cell transplantation methods, including cell type, dose, transplantation route, and transplantation timing, vary widely between trials, and there is no consensus regarding the most effective treatment strategy. This study reviews the current knowledge on this issue, with a special focus on the clinical trials that have used stem cells for treating SCI, and highlights the problems that remain to be solved before the widespread clinical use of stem cells can be adopted.

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Stem Cell Transplantation: A Promising Therapy for Spinal Cord Injury

Current Stem Cell Research & Therapy ◽

10.2174/1574888x14666190823144424 ◽

2020 ◽

Vol 15 (4) ◽

pp. 321-331 ◽

Cited By ~ 2

Author(s):

Zhe Gong ◽

Kaishun Xia ◽

Ankai Xu ◽

Chao Yu ◽

Chenggui Wang ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Therapeutic Potential ◽

Embryonic Stem ◽

Current Status ◽

Cord Injury

Spinal Cord Injury (SCI) causes irreversible functional loss of the affected population. The incidence of SCI keeps increasing, resulting in huge burden on the society. The pathogenesis of SCI involves neuron death and exotic reaction, which could impede neuron regeneration. In clinic, the limited regenerative capacity of endogenous cells after SCI is a major problem. Recent studies have demonstrated that a variety of stem cells such as induced Pluripotent Stem Cells (iPSCs), Embryonic Stem Cells (ESCs), Mesenchymal Stem Cells (MSCs) and Neural Progenitor Cells (NPCs) /Neural Stem Cells (NSCs) have therapeutic potential for SCI. However, the efficacy and safety of these stem cellbased therapy for SCI remain controversial. In this review, we introduce the pathogenesis of SCI, summarize the current status of the application of these stem cells in SCI repair, and discuss possible mechanisms responsible for functional recovery of SCI after stem cell transplantation. Finally, we highlight several areas for further exploitation of stem cells as a promising regenerative therapy of SCI.

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Human-Induced Neural and Mesenchymal Stem Cell Therapy Combined with a Curcumin Nanoconjugate as a Spinal Cord Injury Treatment

International Journal of Molecular Sciences ◽

10.3390/ijms22115966 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5966

Author(s):

Pablo Bonilla ◽

Joaquim Hernandez ◽

Esther Giraldo ◽

Miguel A. González-Pérez ◽

Ana Alastrue-Agudo ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Neural Function ◽

Neuroprotective Effects ◽

Cord Injury

We currently lack effective treatments for the devastating loss of neural function associated with spinal cord injury (SCI). In this study, we evaluated a combination therapy comprising human neural stem cells derived from induced pluripotent stem cells (iPSC-NSC), human mesenchymal stem cells (MSC), and a pH-responsive polyacetal–curcumin nanoconjugate (PA-C) that allows the sustained release of curcumin. In vitro analysis demonstrated that PA-C treatment protected iPSC-NSC from oxidative damage in vitro, while MSC co-culture prevented lipopolysaccharide-induced activation of nuclear factor-κB (NF-κB) in iPSC-NSC. Then, we evaluated the combination of PA-C delivery into the intrathecal space in a rat model of contusive SCI with stem cell transplantation. While we failed to observe significant improvements in locomotor function (BBB scale) in treated animals, histological analysis revealed that PA-C-treated or PA-C and iPSC-NSC + MSC-treated animals displayed significantly smaller scars, while PA-C and iPSC-NSC + MSC treatment induced the preservation of β-III Tubulin-positive axons. iPSC-NSC + MSC transplantation fostered the preservation of motoneurons and myelinated tracts, while PA-C treatment polarized microglia into an anti-inflammatory phenotype. Overall, the combination of stem cell transplantation and PA-C treatment confers higher neuroprotective effects compared to individual treatments.

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Mesenchymal Stem Cell Sheet Promotes Functional Recovery and Palliates Neuropathic Pain in a Subacute Spinal Cord Injury Model

Stem Cells International ◽

10.1155/2021/9964877 ◽

2021 ◽

Vol 2021 ◽

pp. 1-18

Author(s):

Kazuyoshi Yamazaki ◽

Masahito Kawabori ◽

Toshitaka Seki ◽

Soichiro Takamiya ◽

Kotaro Konno ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Neuropathic Pain ◽

Stem Cell ◽

Cell Transplantation ◽

Functional Recovery ◽

Cell Sheet ◽

Histological Evaluation ◽

Cord Injury

Stem cell therapy has been shown to reverse the sequelae of spinal cord injury (SCI). Although the ideal treatment route remains unknown, providing a large number of stem cells to the injured site using less invasive techniques is critical to achieving maximal recovery. This study was conducted to determine whether administration of bone marrow stem cell (BMSC) sheet made on its own without a scaffold is superior to intramedullary cell transplantation in a rat subacute SCI model. Adult female Sprague-Dawley rats were subjected to SCI by 30 g clip compression at the level of Th6 and Th7 and were administered BMSC cell sheet ( 7 × 10 4 cells, subdural), cell suspension ( 7 × 10 4 cells, intramedullary), or control seven days after the injury. Motor and sensory assessments, as well as histological evaluation, were performed to determine the efficacy of the different cell transplantation procedures. While both the cell sheet and cell intramedullary injection groups showed significant motor recovery compared to the control group, the cell sheet group showed better results. Furthermore, the cell sheet group displayed a significant sensory recovery compared to the other groups. A histological evaluation revealed that the cell sheet group showed smaller injury lesion volume, less inflammation, and gliosis compared to other groups. Sensory-related fibers of μ-opioid receptors (MOR, interneuron) and hydroxytryptamine transporters (HTT, descending pain inhibitory pathway), located around the dorsal horn of the spinal cord at the caudal side of the SCI, were preserved only in the cell sheet group. Stem cells could also be found inside the peri-injured spinal cord in the cell sheet group. BMSC cell sheets were able to promote functional recovery and palliate neuropathic pain more effectively than intramedullary injections, thus serving as a good treatment option for SCI.

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Stem Cells Therapy for Spinal Cord Injury: An Overview of Clinical Trials

International Journal of Molecular Sciences ◽

10.3390/ijms21020659 ◽

2020 ◽

Vol 21 (2) ◽

pp. 659 ◽

Cited By ~ 6

Author(s):

Serena Silvestro ◽

Placido Bramanti ◽

Oriana Trubiani ◽

Emanuela Mazzon

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Clinical Trials ◽

Stem Cell ◽

Experimental Studies ◽

Motor Deficits ◽

Safety And Efficacy ◽

Cell Based Therapy ◽

Cord Injury

Spinal cord injury (SCI) is a traumatic lesion that causes disability with temporary or permanent sensory and/or motor deficits. The pharmacological approach still in use for the treatment of SCI involves the employment of corticosteroid drugs. However, SCI remains a very complex disorder that needs future studies to find effective pharmacological treatments. SCI actives a strong inflammatory response that induces a loss of neurons followed by a cascade of events that lead to further spinal cord damage. Many experimental studies demonstrate the therapeutic effect of stem cells in SCI due to their capacity to differentiate into neuronal cells and by releasing neurotrophic factors. Therefore, they appear to be a valid strategy to use in the field of regenerative medicine. The purpose of this paper is to provide an overview of clinical trials, recorded in clinical trial.gov during 2005–2019, aimed to evaluate the use of stem cell-based therapy in SCI. The results available thus far show the safety and efficacy of stem cell therapy in patients with SCI. However, future trials are needed to investigate the safety and efficacy of stem cell transplantation.

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Current status of experimental cell replacement approaches to spinal cord injury

Neurosurgical FOCUS ◽

10.3171/foc/2008/24/3-4/e18 ◽

2008 ◽

Vol 24 (3-4) ◽

pp. E19 ◽

Cited By ~ 65

Author(s):

Eftekhar Eftekharpour ◽

Soheila Karimi-Abdolrezaee ◽

Michael G. Fehlings

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Stem Cell ◽

Current Knowledge ◽

Embryonic Stem ◽

Current Status ◽

Human Stem Cells ◽

Cell Replacement ◽

Cord Injury

✓ Despite advances in medical and surgical care, the current clinical therapies for spinal cord injury (SCI) are largely ineffective. During the last 2 decades, the search for new therapies has been revolutionized by the discovery of stem cells, which has inspired scientists and clinicians to search for a stem cell–based reparative approaches to many diseases, including neurotrauma. In the present study, the authors briefly summarize current knowledge related to the pathophysiology of SCI, including the concepts of primary and secondary injury and the importance of posttraumatic demyelination. Key inhibitory obstacles that impede axonal regeneration include the glial scar and a number of myelin inhibitory molecules including Nogo. Recent advancements in cell replacement therapy as a therapeutic strategy for SCI are summarized. The strategies include the use of pluripotent human stem cells, embryonic stem cells, and a number of adult-derived stem and progenitor cells such as mesenchymal stem cells, Schwann cells, olfactory ensheathing cells, and adult-derived neural precursor cells. Although current strategies to repair the subacutely injured cord appear promising, many obstacles continue to render the treatment of chronic injuries challenging. Nonetheless, the future for stem cell–based reparative strategies for treating SCI appears bright.

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Stem Cell Clinical Trials in Spinal Cord Injury: A Brief Review of Studies in the United States

Medicines ◽

10.3390/medicines7050027 ◽

2020 ◽

Vol 7 (5) ◽

pp. 27

Author(s):

Andrew Platt ◽

Brian T. David ◽

Richard G. Fessler

Keyword(s):

United States ◽

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Clinical Trials ◽

Stem Cell ◽

Intrathecal Injection ◽

Embryonic Stem ◽

The United States ◽

Cord Injury

Background: Although many therapeutic approaches have been attempted to treat spinal cord injury, cellular transplantation offers the greatest promise in reconstituting the architecture of the damaged cord. Methods: A literature review was conducted to search for clinical trials investigating stem cells as treatment for spinal cord injury in the United States. Results: Overall, eight studies met inclusion criteria. Of the included studies, four were identified as being terminated, suspended, or not yet recruiting. Two studies were identified as currently recruiting, including one phase one trial evaluating stereotactic injections of human spinal cord-derived neural stem cells in patients with chronic spinal cord injuries, and one trial of transplantation of autologous bone marrow derived stem cells via paraspinal injections, intravenous injections, and intranasal placement. One study was identified as an active study, a phase one trial of intrathecal injection of 100 million autologous, ex-vivo expanded, adipose-derived mesenchymal stem cells. One trial that was listed as completed is a phase 1/2a, dose escalation study, investigating stereotactic injection of human embryonic stem cell derived oligodendrocyte progenitor cells. Conclusions: Although few significant publications have emerged to this point, current trial results are promising.

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Evaluation of the Clinical Efficacy of Stem Cell Transplantation in the Treatment of Spinal Cord Injury: A Systematic Review and Meta-analysis

Cell Transplantation ◽

10.1177/09636897211067804 ◽

2021 ◽

Vol 30 ◽

pp. 096368972110678

Author(s):

Qiao-Rui Tang ◽

Hui Xue ◽

Qiao Zhang ◽

Ying Guo ◽

Hao Xu ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Bone Marrow ◽

Spinal Cord Injury ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Treatment Time ◽

Cell Numbers ◽

Cord Injury

Stem cell transplantation has been applied to treat spinal cord injury (SCI) in clinical trials for many years. However, the clinical efficacies of stem cell transplantation in SCI have been quite diverse. The purpose of our study was to systematically investigate the efficacy of stem cell transplantation in patients with SCI. The PubMed, Web of Science, Ovid-Medline, Cochrane Library, China National Knowledge Infrastructure, VIP, Wanfang, and SinoMed databases were searched until October 27, 2020. Quantitative and qualitative data were analyzed by Review Manager 5.3 and R. Nine studies ( n = 328) were included, and the overall risk of bias was moderate. The ASIA Impairment Scale (AIS) grading improvement rate was analyzed in favor of stem cell transplantation group [odds ratio (OR) = 6.06, 95% confidence interval (CI): 3.16–11.62, P < 0.00001]. Urodynamic indices also showed improvement in bladder function. In subgroup analyses, the results indicated that in patients with complete (AIS A) SCI, with the application of cell numbers between n*(107–108), two cell types (i.e., bone marrow–derived mesenchymal stem cells and bone marrow mononuclears), and treatment time of more than 6 months, stem cell transplantation was more beneficial for sensorimotor function ( P < 0.05 for all groups). The risk of fever incidence in the stem cell transplantation group was 4.22 (95% CI: 1.7–10.22, P = 0.001), and principal component analysis (PCA) suggested it was more related to transplanted cell numbers. Thus, stem cell transplantation can promote functional recovery in SCI patients. Moreover, the type and quantity of transplanted stem cells and treatment time are important factors affecting the therapeutic effect of stem cell transplantation in SCI. Further studies are needed to evaluate the effects and elucidate the mechanisms of these factors on stem cell therapy in SCI.

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Effect of neural stem cell transplantation combined with erythropoietin injection on axon regeneration in adult rats with transected spinal cord injury

Genetics and Molecular Research ◽

10.4238/2015.december.22.4 ◽

2015 ◽

Vol 14 (4) ◽

pp. 17799-17808 ◽

Cited By ~ 7

Author(s):

Y. Zhao ◽

Y. Zuo ◽

X.L. Wang ◽

H.J. Huo ◽

J.M. Jiang ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Neural Stem Cell ◽

Axon Regeneration ◽

Adult Rats ◽

Cord Injury

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Review of clinical trials of neuroprotection in acute spinal cord injury

Neurosurgical FOCUS ◽

10.3171/foc.1999.6.1.11 ◽

1999 ◽

Vol 6 (1) ◽

pp. E10 ◽

Cited By ~ 8

Author(s):

Charles H. Tator ◽

Michael G. Fehlings

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Clinical Trials ◽

Treatment Time ◽

Time Window ◽

Current Knowledge ◽

Acute Spinal Cord Injury ◽

Randomized Controlled Studies ◽

Cord Injury ◽

Therapeutic Time Window

In this paper the authors review the clinical trials of neuroprotection that have been performed for the treatment of acute spinal cord injury (SCI). The biological rationale for the selection of each treatment modality is discussed with reference to current knowledge of the principles in the management of acute SCI as well as the primary and secondary injury mechanisms identified by experimental and clinical studies of the pathophysiology of acute SCI. The trials are evaluated with regard to the availability and use of accurate clinical outcome measures, and the methodologies of the trials are critically evaluated with an emphasis on prospective randomized controlled studies. A detailed description and critical analysis are provided of the results of the 10 clinical trials conducted to date in which a randomized prospective controlled design has been used. The issue of the therapeutic time window in acute SCI is discussed. To date, methylprednisolone is the only effective neuroprotective agent that has been established for use in human SCI, and the only therapeutic time window established in human SCI is a maximum trauma-to-treatment time of 8 hours.

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