A meta-analysis of efficacy in pre-clinical human stem cell therapies for traumatic brain injury

Chang, Janessa; Phelan, Michael; Cummings, Brian J.

doi:10.1016/j.expneurol.2015.08.020

Cited by 26 publications

(24 citation statements)

References 35 publications

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“…In the analysis by Peng et al (55) only behavioral data were extracted from studies in animals that received only human mesenchymal stromal cells (hMSC), limiting the number of studies that could be included. In the meta-analysis by Chang et al (56) studies were included that examined modified and naïve progenitor cells for the treatment of traumatic brain injury. This was not the primary endpoint of our authors, and so this study has a different population of studies included for analysis.…”

Section: Discussionmentioning

confidence: 99%

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Preclinical progenitor cell therapy in traumatic brain injury: a meta-analysis

Jackson

Srivastava

Cox

2017

Journal of Surgical Research

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Background: No treatment is available to reverse injury associated with traumatic brain injury (TBI). Progenitor cell therapies show promise in both pre-clinical and clinical studies. We conducted a meta-analysis of pre-clinical studies using progenitor cells to treat TBI. Methods: EMBASE, MEDLINE, Cochrane Review, Biosis, and Google Scholar were searched for articles using pre-specified search strategies. Studies meeting inclusion criteria underwent data extraction. Analysis was performed using Review Manager 5.3 according to a fixed-effects model, and all studies underwent quality scoring. Results: Of 430 abstracts identified, 38 met inclusion criteria and underwent analysis. Average quality score was 4.32 out of 8 possible points. No study achieved a perfect score. Lesion volume (LV) and Neurologic Severity Score (NSS) outcomes favored cell treatment with standard mean difference (SMD) of 0.86 (95%CI 0.64, 1.09) and 1.36 (95%CI 1.11, 1.60) respectively. Rotarod (RR) and Morris Water Maze (MWM) outcomes also favored treatment with improvements in SMD of 0.34 (95%CI 0.02, 0.65) and 0.46 (95%CI 0.17, 74) respectively. While LV and NSS were robust to publication bias assessments, RR and MWM were not. Heterogeneity (I2) ranged from 74% to 85% among the analyses, indicating a high amount of heterogeneity among studies. Precision as a function of quality score showed a statistically significant increase in the size of the confidence interval as quality improved. Conclusions: Our meta-analysis study reveals an overall positive effect of progenitor cell therapies on LV and NSS with a trend towards improved motor function and spatial learning in different TBI animal models.

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Section: Discussionmentioning

confidence: 99%

“…In the meta-analysis by Chang et al ., higher quality index scores were associated with smaller MWM treatment effect sizes, but greater precision (56). Peng et al .…”

Section: Discussionmentioning

confidence: 99%

Preclinical progenitor cell therapy in traumatic brain injury: a meta-analysis

Jackson

Srivastava

Cox

2017

Journal of Surgical Research

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“…30,[76][77][78] In other TBI and stroke models, cells have been delivered via intravenous (IV), intra-arterial carotid (IAC) or intraparenchymal (IP) injections. However, IV administration causes loss of the majority (~95%) of the cells during lung passage, 55,[79][80][81] whereas IAC injection carries the risk of causing embolic brain infarction and fails to deliver sufficient cells across the vascular wall barrier to the brain parenchyma, which is the major barrier for putative clinical use of this route. Engraftment after IAC injection is also dependent on cell type and adhesion molecule expression.…”

Section: 75mentioning

confidence: 99%

“…1,55 Further the experts in the field recommended that 8-week survival period prior to assessments would allow sufficient time for differentiation and integration of human neural stem cells with the host and possibly validate the presumed mechanism of action.…”

Section: -50mentioning

confidence: 99%

“…53,54 A review of literature shows human cell therapy in rat TBI that measure cognitive benefit have not addressed donor cell fate past one-month posttransplantation. 1,55 Further the experts in the field recommended that 8-week survival period prior to assessments would allow sufficient time for differentiation and integration of human neural stem cells with the host and possibly validate the presumed mechanism of action. 1,26 The successful preclinical ALS, SCI and stroke studies.…”

Section: Step 2 Immunosuppressionmentioning

confidence: 99%

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One Step at a Time, Stem Cell Therapy for Traumatic Brain Injury Needs Two More Breakthroughs

Gajavelli¹

2016

JSRT

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26As of 2015, a total of 49 ALS patients have received NSI-566 cells. Both the cells and surgery were well tolerated and the ALS studies reported a 47% responder rate with decline in disease progression and improved grip strength. Stem cells inc., on the other hand lost a patent dispute to NSI and recently closed operations.J Stem Cell Res Ther. 2016;1(4):160-164. 160© 2016 Shyam. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and build upon your work non-commercially.One step at a time, stem cell therapy for traumatic brain injury needs two more breakthroughs Step 2 ImmunosuppressionTransplantation of the cells conferred benefits such as restoration of injured neuronal morphology 45 and cognitive function. 46 even without immunosuppression. Transient immunosuppression was shown to be sufficient to support engraftment and transplanted derived neurons were reportedly present 6 months post transplantation. 47 However, no data quantifying either engraftment or behavior modification were presented. Such studies were limited by cyclosporine mediated immunosuppression which resulted in persistence of barriers to engraftment and demonstration of effectiveness of the approach. 48-50The initial optimism was replaced by skepticism if the therapeutic potential of neural stem cells: greater in people's perception than in their brains. 51,52 The US Food and Drug Administration (FDA; Rockville, MD) guidelines on preclinical assessment of cell therapies in the publication "Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products".53,54 A review of literature shows human cell therapy in rat TBI that measure cognitive benefit have not addressed donor cell fate past one-month posttransplantation. 1,55 Further the experts in the field recommended that 8-week survival period prior to assessments would allow sufficient time for differentiation and integration of human neural stem cells with the host and possibly validate the presumed mechanism of action. 1,26The successful preclinical ALS, SCI and stroke studies. 40,41,44,56 have employed a different immunosuppression technique that was pioneered by Hefferan et al. 40 This technique relies on three agents namely: mycophenylate mofetil, tacrolimus and methyl prednisolone. The combination has been found to be superior to cyclosporine, a standard immunosuppressant between 1999-2012. Step 3 Mechanism of actionHowever, due to the lack of exact mechanism of action still precludes attempts to move neural stem cell therapy to the clinic. 26Paul Lu et al. 41 demonstrated the mechanism of regeneration in spinal cord injury models. 41 Axonal growth was partially dependent on mammalian target of rapamycin (mTOR), but not Nogo signaling. Grafted neurons supported formation of electrophysiological relays across sites of complete spinal transection, resulting in functional recovery. The recovery was lost subsequent to re-transection of the spinal cord....

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Evaluation of Evidence: Stem Cells as a Treatment Option for Traumatic Brain Injury

Tabet

Hasan

Abdelhady

et al. 2020

Encyclopedia of Life Sciences

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Traumatic brain injury (TBI) is a major public health concern. TBI has two phases: a primary injury due to direct damage from a mechanical force applied to the head and a secondary injury due to cellular and molecular responses to the injury. Despite its significant burden on societies, decades of clinical trials have not yielded any FDA‐approved therapies for TBI. Insignificant endogenous repair and continued neuronal cell loss underlie the disability in TBI survivors. The advent of stem cell culture led to the notion that such cells could potentially replace lost cells. Examination of preclinical and clinical studies suggests that stem cell‐replacement approaches in TBI remain elusive. In contrast, stem cell transplantation appears to mitigate multiple TBI‐induced pathologies by modulating inflammation, angiogenesis and endogenous neurogenesis. Thus, transplantation‐based stem cell therapeutic approaches are a viable treatment option for TBI. Key Concepts Traumatic brain injury (TBI) is a major health concern with complex underlying pathology mechanisms and no FDA‐approved treatments to date. Stem cells, which can be obtained from different sources, have therapeutic properties that render them beneficial for treating various neurological and neurodegenerative diseases, including TBI. Stem cell‐based therapy has been utilised for the treatment of TBI and has shown to be a therapeutic promise in few preclinical and early phase clinical studies. Neural stem cells have neuro‐restorative properties that are promising for the treatment of various neurological and neurodegenerative disorders. Despite their promising therapeutic abilities, stem cell‐based therapies still face several hurdles that limit their efficacy as a treatment in TBI. More research is needed to perfect this treatment approach.

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A meta-analysis of efficacy in pre-clinical human stem cell therapies for traumatic brain injury

Cited by 26 publications

References 35 publications

Preclinical progenitor cell therapy in traumatic brain injury: a meta-analysis

Preclinical progenitor cell therapy in traumatic brain injury: a meta-analysis

One Step at a Time, Stem Cell Therapy for Traumatic Brain Injury Needs Two More Breakthroughs

Evaluation of Evidence: Stem Cells as a Treatment Option for Traumatic Brain Injury

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