Preclinical efficacy and clinical safety of clinical‐grade nebulized allogenic adipose mesenchymal stromal cells‐derived extracellular vesicles

Abstract

Mesenchymal stromal cell‐derived extracellular vesicles (MSC‐EVs) turn out to be a promising source of cell‐free therapy. Here, we investigated the biodistribution and effect of nebulized human adipose‐derived MSC‐EVs (haMSC‐EVs) in the preclinical lung injury model and explored the safety of nebulized haMSC‐EVs in healthy volunteers. DiR‐labelled haMSC‐EVs were used to explore the distribution of nebulized haMSC‐EVs in the murine model. Pseudomonas aeruginosa‐induced murine lung injury model was established, and survival rate, as well as WBC counts, histology, IL‐6, TNF‐α and IL‐10 levels in bronchoalveolar lavage fluid (BALF) were measured to explore the optimal therapeutic dose of haMSC‐EVs through the nebulized route. Twenty‐four healthy volunteers were involved and received the haMSC‐EVs once, ranging from 2 × 108 particles to 16 × 108 particles (MEXVT study, NCT04313647). Nebulizing haMSC‐EVs improved survival rate to 80% at 96 h in P. aeruginosa‐induced murine lung injury model by decreasing lung inflammation and histological severity. All volunteers tolerated the haMSC‐EVs nebulization well, and no serious adverse events were observed from starting nebulization to the 7th day after nebulization. These findings suggest that nebulized haMSC‐EVs could be a promising therapeutic strategy, offering preliminary evidence to promote the future clinical applications of nebulized haMSC‐EVs in lung injury diseases.

Mesenchymal Stem Cell-Derived Extracellular Vesicles in Liver Immunity and Therapy

“…In this research, the authors reported that no adverse events were observed within 72 h of MSC-EV intravenous injection, and MSC-EV treatment improved oxygenation, downregulated the cytokine storm, and reconstituted immunity. Another study also verified the safety of nebulized clinical-grade (211). However, there is no registered clinical research on clinical trials focusing on MSC-EVs in liver diseases.…”

Mesenchymal Stem Cell-Derived Exosome Therapy of Microbial Diseases: From Bench to Bed

“…Accumulating evidence has demonstrated that MSC-Exo therapy is effective in attenuating excessive inflammation, restoring pulmonary function, and reducing mortality, verified in several typical ARDS/ALI animal models (Kannan et al, 2009;Knapp, 2009;Islam et al, 2012;Zhu et al, 2014;Hraiech et al, 2015;Monsel et al, 2015;Ogata-Suetsugu et al, 2017;Hao et al, 2019;Domscheit et al, 2020;Metcalfe, 2020;Wang et al, 2020a;Kaspi et al, 2021;Shi et al, 2021a;Tieu et al, 2021). Herein, the following portion aims at providing a comprehensive understanding of therapeutical mechanisms of MSC-Exos on bacteria/ viruses-induced pneumonia.…”

“…Within 2 × 10 5 to 2 × 10 6 particles per administration, mice survival rates and EV dosage were positively correlated. However, once exceeding the dose of 2 × 10 6 particles, ADSC-EVs posed an adverse effect on the survival rate ( Shi et al, 2021a ). A numerically lower influx of neutrophils was also seen in an ex vivo perfused human lung injured with severe E. coli pneumonia, after MSC-MV treatment ( Park et al, 2019 ).…”

Adipose Tissue-Derived Mesenchymal Stem/Stromal Cells and Their Contribution to Angiogenic Processes in Tissue Regeneration

“…There are also two completed clinical trials exploring the safety and efficiency of AT-MSC exosomes used as aerosol inhalation (NCT04313647) and for the treatment of patients hospitalized with coronavirus pneumonia (NCT04276987). The first study (NCT04313647) proved that aerosol inhalation of AT-MSCs-derived exosomes is safe and does not cause serious adverse events in healthy volunteers [ 109 ]. The second one (NCT04276987) was a pilot clinical trial performed to explore the safety and efficiency of aerosol inhalation of the exosomes derived from allogenic adipose MSCs (MSCs-Exo) in patients with severe novel coronavirus pneumonia (NCP).…”