Safety of Intraparenchymal Injection of Allogenic Placenta Mesenchymal Stem Cells Derived Exosome in Patients Undergoing Decompressive Craniectomy Following Malignant Middle Cerebral Artery Infarct, A Pilot Randomized Clinical Trial

Abstract

Background: Malignant middle cerebral artery infarct (mMCAI) largely contributes to high mortality and physical disability among adults. Surviving individuals may not have proper outcomes and suffer from severe lasting disabilities. Utilization of stem cells and paracrine factor for regenerative purposes is considered as a potential strategy for patients with neurological deficits. While preclinical stroke studies have shown that mesenchymal stem cells (MSCs) reduce post-treatment neurological deficits and prevent disability and also promote recovery, few randomized clinical trials (RCT) have assessed exosome therapy in humans. Methods: In this RCT, we assessed the safety of intraparenchymal injection placenta MSC-derived Exosome in mMCAI patients with average age of 62 years between January, 2019, till September, 2020. The study was done in a single-center as an open-label RCT, with a 3-months follow-up. Primary outcomes assessed the safety and also disability indexes were followed. Results: Five mMCAI patients were included with mean NIHSS: 17.6 ± 5.02. The mean MRS was 3.25 ± 0.95 in three patients. No serious adverse events were observed. Hematoma or local reaction as excessive edema were not seen at the site of injection. Conclusions: Intraparenchymal implantation of MSC-EXO showed no post-interventional adverse effects in five ischemic stroke patients. It is proposed Local injection Exosome treatment following mMCAI can be safe and in future, it would be applied as a supportive, restorative and preventive treatment in patients who suffer from acute ischemic stroke and post ischemic disability.

Marrow Mesenchymal Stem Cell-Derived Exosomes Upregulate Astrocytic Glutamate Transporter-1 Expression via miR-124/mTOR Pathway against Oxygen-Glucose Deprivation/Reperfusion Injury

“…Rodent studies have proved that MSC-Exos are effective treatment for ischemic stroke, which could attenuate cerebral infarction area, reduce neurological damage, and rescue synaptic communication, neuronal plasticity, spatial memory, and learning [19,20]. A recent clinical trial also confirmed the safety and feasibility of intraparenchymal injection of MSC-Exos in the treatment of ischemic stroke [21]. Nevertheless, the therapeutic mechanisms of MSC-Exo in the treatment of ischemic stroke are far from clear, which limits its clinical application and development.…”

A systematic review and meta‐analysis of clinical trials assessing safety and efficacy of human extracellular vesicle‐based therapy

“…Despite numerous technological advances, there is still an urgent need for new therapeutic strategies in the field of regenerative medicine. In this systematic review, five studies were included evaluating the use of therapeutic EVs for the purpose of regeneration in stroke (Dehghani et al., 2022 ), wound healing (Johnson et al., 2023 ), sensitive skin (Ye et al., 2022 ),the healing of refractory macular holes (Zhang et al., 2018 ), and chronic venous ulcers (Gibello et al, 2023 ).…”

“…In a prospective phase I clinical trial by Dehghani et al. ( 2022 ), the use of allogeneic MSC‐derived EVs was evaluated for the treatment post decompressive craniectomy in patients with malignant middle cerebral artery infarct. Treatment was administered via a single dose intraparenchymal injection.…”

“…Improvements were seen in four out of five patients on several clinical measures, such as the modified Rankin Scale, NIH Stroke Scale and CRP. However, since this trial had a single‐arm study design with a focus on safety and feasibility, these efficacy results are not reliable enough to discuss the effectiveness of the treatment (Dehghani et al., 2022 ). No follow‐up studies on the products were found.…”

Local Delivery Strategies for Peptides and Proteins into the CNS: Status Quo, Challenges, and Future Perspectives

“…EVs themselves have been used for the treatment of CNS diseases and showed good safety. Intraparenchymal administration of exosomes extracted from allogenic placenta mesenchymal stem cells showed good safety in malignant middle cerebral artery infarct patients in a pilot randomized clinical trial [ 94 ]. In an ongoing clinical trial, safety and efficacy of EVs derived from allogenic adipose mesenchymal stem cells through IN administration are being tested for the treatment of mild to moderate dementia [ 95 ].…”