Nebulized exosomes derived from allogenic adipose tissue mesenchymal stromal cells in patients with severe COVID-19: a pilot study

Ying-Gang Zhu, Meng-Meng Shi, Antoine Monsel, Cheng-Xiang Dai, Xuan Dong, Hong Shen, Su-Ke Li, Jing Chang, Cui-Li Xu, Ping Li, Jing Wang, Mei-Ping Shen, Cheng-Jie Ren, De-Chang Chen, Jie-Ming Qu, Ying-Gang Zhu, Meng-Meng Shi, Antoine Monsel, Cheng-Xiang Dai, Xuan Dong, Hong Shen, Su-Ke Li, Jing Chang, Cui-Li Xu, Ping Li, Jing Wang, Mei-Ping Shen, Cheng-Jie Ren, De-Chang Chen, Jie-Ming Qu

Abstract

Background: Existing clinical studies supported the potential efficacy of mesenchymal stromal cells as well as derived exosomes in the treatment of COVID-19. We aimed to explore the safety and efficiency of aerosol inhalation of the exosomes derived from human adipose-derived MSCs (haMSC-Exos) in patients with COVID-19.

Methods: The MEXCOVID trial is a phase 2a single-arm, open-labelled, interventional trial and patients were enrolled in Jinyintan Hospital, Wuhan, China. Eligible 7 patients were assigned to receive the daily dose of haMSCs-Exos (2.0 × 108 nano vesicles) for consecutively 5 days. The primary outcomes included the incidence of prespecified inhalation-associated events and serious adverse events. We also observed the demographic data, clinical characteristics, laboratory results including lymphocyte count, levels of D-dimer and IL-6 as well as chest imaging.

Results: Seven severe COVID-19 related pneumonia patients (4 males and 3 females) were enrolled and received nebulized haMSC-Exos. The median age was 57 year (interquartile range (IQR), 43 year to 70 year). The median time from onset of symptoms to hospital admission and administration of nebulized haMSC-Exos was 30 days (IQR, 15 days to 40 days) and 54 d (IQR, 34 d to 69 d), respectively. All COVID-19 patients tolerated the haMSC-Exos nebulization well, with no evidence of prespecified adverse events or clinical instability during the nebulization or during the immediate post-nebulization period. All patients presented a slight increase of serum lymphocyte counts (median as 1.61 × 109/L vs. 1.78 × 109/L). Different degrees of resolution of pulmonary lesions after aerosol inhalation of haMSC-Exos were observed among all patients, more obviously in 4 of 7 patients.

Conclusions: Our trial shows that a consecutive 5 days inhalation dose of clinical grade haMSC-Exos up to a total amount of 2.0 × 109 nano vesicles was feasible and well tolerated in seven COVID-19 patients, with no evidence of prespecified adverse events, immediate clinical instability, or dose-relevant toxicity at any of the doses tested. This safety profile is seemingly followed by CT imaging improvement within 7 days. Further trials will have to confirm the long-term safety or efficacy in larger population.

Trial registration: MEXCOVID, NCT04276987.

Keywords: COVID-19; Exosomes; Extracellular vesicles; Inhalation; Mesenchymal stromal cell.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Clinical characters of patients in the MEXCOVID study. A Temperature B heart rate C respiratory rate D oxyhemoglobin saturation before and after hMSC-Exos nebulization in COVID-19 patients. E–J Dynamic changes of laboratory parameters before and after haMSC-Exos nebulization in COVID-19 patients. K Chest CT score before and after haMSC-Exos nebulization in COVID-19 patients. The dotted horizontal line represents the reference value range. haMSC-Exos human adipose-derived MSCs-Exosomes; COVID-19 coronavirus disease 2019; Lym lymphocyte; CRP C reactive protein; IL-6 Interleukin-6; LDH Lactate dehydrogenase; ALT alanine aminotransferase; Cr: creatinine
Fig. 2
Fig. 2
Clinical improvement from baseline, the onset day of inhalation treatment, in individual patients in the MEXCOVID study. A Changes in oxygen-support status from baseline in individual patients. B Cumulative incidence of clinical improvement from the onset of neublization. C–F Changes of chest CT scan before and after haMSC-Exos inhalation in COVID-19 patients
Fig. 3
Fig. 3
Dynamic changes of laboratory parameters in patient 4 and patient 6 before and after haMSC-Exos nebulization. The dotted horizontal line represents the reference value range. Lym lymphocyte; CRP C reactive protein; IL-6 interleukin-6; ALT alanine aminotransferase; Cr creatinine; LDH lactate dehydrogenase

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