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

J Extracell Vesicles. 2021 Aug;10(10):e12134. doi: 10.1002/jev2.12134. Epub 2021 Aug 14.

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.

Keywords: extracellular vesicles; healthy volunteers; lung injury; mesenchymal stromal cells; nebulization.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Bronchoalveolar Lavage Fluid / chemistry
  • Cell- and Tissue-Based Therapy / methods*
  • Cytokines / metabolism*
  • Disease Models, Animal
  • Drug Evaluation, Preclinical*
  • Extracellular Vesicles / physiology*
  • Female
  • Humans
  • Lung Injury / microbiology
  • Lung Injury / therapy*
  • Male
  • Mesenchymal Stem Cells / physiology*
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Middle Aged
  • Patient Safety
  • Pseudomonas Infections / microbiology
  • Pseudomonas aeruginosa
  • Survival Rate
  • Therapeutics / methods
  • Young Adult

Substances

  • Cytokines

Associated data

  • ClinicalTrials.gov/NCT04313647