The effects of intravenous infusion of autologous mesenchymal stromal cells in patients with subacute middle cerebral artery infarct: a phase 2 randomized controlled trial on safety, tolerability and efficacy

Law, Zhe Kang; Tan, Hui Jan; Chin, S.; Wong, Chee-Yin; Yahya, Wan Nur Nafisah Wan; Muda, Ahmad Sobri; Zakaria, Ros Mahwati Ahmad; Ariff, Mohammed; Ismail, Nor Azimah; Cheong, Soon Keng; Fadilah, S A W; Ibrahim, Norlinah Mohamed

doi:10.1016/j.jcyt.2021.03.005

Cited by 36 publications

(47 citation statements)

References 42 publications

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“…The results also showed that MSCs were safe and could promote functional recovery depending on the specific characteristics of the patients, and associated with serum levels of stromal cell-derived factor-1 and the degree of involvement of the subventricular region of the lateral ventricle [ 17 ]. Subsequently, two phase II trials from Jaillard et al and Law ZK et al also confirmed the safety and feasibility of MSCs in subacute stroke [ 18 , 19 ]. Similarly, studies for the treatment of chronic stroke have demonstrated the safety, feasibility, and therapeutic effects of MSCs [ 20 ].…”

Section: Safety Feasibility and Efficacy Of Msc Transplantation For I...mentioning

confidence: 95%

Potential mechanisms and therapeutic targets of mesenchymal stem cell transplantation for ischemic stroke

et al. 2022

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Ischemic stroke is one of the major causes of death and disability in the world. Currently, most patients cannot choose intravenous thrombolysis or intravascular mechanical thrombectomy because of narrow therapeutic windows and severe complications. Stem cell transplantation is an emerging treatment and has been studied in various central nervous system diseases. Animal and clinical studies showed that transplantation of mesenchymal stem cells (MSCs) could alleviate neurological deficits and bring hope for ischemic stroke treatment. This article reviewed biological characteristics, safety, feasibility and efficacy of MSCs therapy, potential therapeutic targets of MSCs, and production process of Good Manufacturing Practices-grade MSCs, to explore the potential therapeutic targets of MSCs in the process of production and use and provide new therapeutic directions for ischemic stroke.

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Section: Safety Feasibility and Efficacy Of Msc Transplantation For I...mentioning

confidence: 95%

Potential mechanisms and therapeutic targets of mesenchymal stem cell transplantation for ischemic stroke

et al. 2022

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“…The second screening discarded 60 additional records due to fulfillment of various exclusion criteria. A total of 35 studies remained for safety analysis ( 14 – 48 ) and 19 studies for the combined efficacy and safety analysis ( 49 – 67 ). A summary of the risk of bias for the studies included in the efficacy and safety analysis is shown in Figure 2 .…”

Section: Resultsmentioning

confidence: 99%

“…In total, 26 of the included studies assessed TSCI ( 14 – 16 , 18 – 32 , 49 – 55 ), 19 MS ( 33 – 44 , 56 – 62 ) and 9 IS ( 45 – 48 , 63 – 67 ). Study characteristics are shown in Table 1 .…”

Section: Resultsmentioning

confidence: 99%

Safety and Clinical Efficacy of Mesenchymal Stem Cell Treatment in Traumatic Spinal Cord Injury, Multiple Sclerosis and Ischemic Stroke – A Systematic Review and Meta-Analysis

et al. 2022

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BackgroundMesenchymal stem cells (MSCs) is an attractive candidate in regenerative research and clinical trials have assessed their therapeutic potential in different neurological conditions with disparate etiologies. In this systematic review, we aimed to assess safety and clinical effect of MSC treatment in traumatic spinal cord injury (TSCI), multiple sclerosis (MS) and ischemic stroke (IS).MethodsA systematic search was performed 2021-12-10 in MEDLINE, EMBASE, Web of Science and Cochrane where clinical studies assessing MSC treatment in TSCI, MS or IS were included. Studies without control group were excluded for efficacy analysis, but included in the safety analysis. For efficacy, AIS score, EDSS score and mRS were used as clinical endpoints and assessed in a meta-analysis using the random effects model.FindingsOf 5,548 identified records, 54 studies were included. Twenty-six studies assessed MSC treatment in TSCI, 14 in MS and nine in IS, of which seven, seven and five studies were controlled, respectively. There were seven serious adverse events (SAEs), of which four were related to the surgical procedure and included one death due to complications following the implantation of MSCs. Three SAEs were considered directly related to the MSC treatment and all these had a transient course. In TSCI, a meta-analysis showed no difference in conversion from AIS A to C and a trend toward more patients treated with MSCs improving from AIS A to B as compared to controls (p = 0.05). A subgroup analysis performed per protocol, showed more MSC treated patients improving from AIS A to C in studies including patients within 8 weeks after injury (p = 0.04). In MS and IS, there were no significant differences in clinical outcomes between MSC treated patients and controls as measured by EDSS and mRS, respectively.InterpretationMSC-treatment is safe in patients with TSCI, MS and IS, although surgical implantation of MSC led to one fatal outcome in TSCI. There was no clear clinical benefit of MSC treatment, but this is not necessarily a proof of inefficacy due to the low number of controlled studies. Future studies assessing efficacy of MSC treatment should aim to do this in randomized, controlled studies.

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“…MSCs have paracrine and immune regulation functions, which can change the microenvironment of damaged brain tissue and transforms it to a more regenerative and less inflammatory environment. MSCs can promote cell migration, angiogenesis, immune regulation, nerve protection, and nerve circuit reconstruction ( Law et al, 2021 ). Moreover, many preclinical research evidences have demonstrated that MSCs promote the clinical transformation of MSCs in the treatment of IS.…”

Section: Novel Application Of Stem Cells In Clinical Treatmentmentioning

confidence: 99%

“…Moreover, intravenous injection of MSCs has been proven to be safe, well tolerated, and relatively feasible. However, several common limitations exist for current RCTs, such as small sample size ( Law et al, 2021 ), long-term waiting for MSC culture, delayed assessment of the treatment group, age of participants, randomization time, heterogeneity of ischemic brain injury site, and severity ( Chung et al, 2021 ). Therefore, further randomized, double-blind, large-scale clinical trials are necessary to evaluate the long-term efficacy and safety of this treatment method.…”

Section: Novel Application Of Stem Cells In Clinical Treatmentmentioning

confidence: 99%

Exosomes Derived From Mesenchymal Stem Cells: Novel Effects in the Treatment of Ischemic Stroke

et al. 2022

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Ischemic stroke is defined as an infarction in the brain, caused by impaired cerebral blood supply, leading to local brain tissue ischemia, hypoxic necrosis, and corresponding neurological deficits. At present, revascularization strategies in patients with acute ischemic stroke include intravenous thrombolysis and mechanical endovascular treatment. However, due to the short treatment time window (<4.5 h) and method restrictions, clinical research is focused on new methods to treat ischemic stroke. Exosomes are nano-sized biovesicles produced in the endosomal compartment of most eukaryotic cells, containing DNA, complex RNA, and protein (30–150 nm). They are released into surrounding extracellular fluid upon fusion between multivesicular bodies and the plasma membrane. Exosomes have the characteristics of low immunogenicity, good innate stability, high transmission efficiency, and the ability to cross the blood–brain barrier, making them potential therapeutic modalities for the treatment of ischemic stroke. The seed sequence of miRNA secreted by exosomes is base-paired with complementary mRNA to improve the microenvironment of ischemic tissue, thereby regulating downstream signal transduction activities. With exosome research still in the theoretical and experimental stages, this review aims to shed light on the potential of exosomes derived from mesenchymal stem cells in the treatment of ischemic stroke.

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The effects of intravenous infusion of autologous mesenchymal stromal cells in patients with subacute middle cerebral artery infarct: a phase 2 randomized controlled trial on safety, tolerability and efficacy

Cited by 36 publications

References 42 publications

Potential mechanisms and therapeutic targets of mesenchymal stem cell transplantation for ischemic stroke

Potential mechanisms and therapeutic targets of mesenchymal stem cell transplantation for ischemic stroke

Safety and Clinical Efficacy of Mesenchymal Stem Cell Treatment in Traumatic Spinal Cord Injury, Multiple Sclerosis and Ischemic Stroke – A Systematic Review and Meta-Analysis

Exosomes Derived From Mesenchymal Stem Cells: Novel Effects in the Treatment of Ischemic Stroke

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