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. 2024 Oct;13(10):e12510.
doi: 10.1002/jev2.12510.

A critical systematic review of extracellular vesicle clinical trials

Rachel R Mizenko  1 , Madison Feaver  1 , Batuhan T Bozkurt  1 , Neona Lowe  1 , Bryan Nguyen  1 , Kuan-Wei Huang  1 , Aijun Wang  1   2 , Randy P Carney  1
Affiliations

A critical systematic review of extracellular vesicle clinical trials

Rachel R Mizenko et al. J Extracell Vesicles. 2024 Oct.

Abstract

This systematic review examines the landscape of extracellular vesicle (EV)-related clinical trials to elucidate the field's trends in clinical applications and EV-related methodologies, with an additional focus on the acknowledgement of EV subpopulations. By analysing data from public reporting repositories, we catalogued 471 EV-related clinical trials to date, with indications for over 200 diseases. Diagnostics and companion diagnostics represented the bulk of EV-related clinical trials with cancer being the most frequent application. EV-related therapeutics trials mainly utilized mesenchymal stromal cell (MSC) EVs and were most frequently used for treatment of respiratory illnesses. Ultracentrifugation and RNA-sequencing were the most common isolation and characterization techniques; however, methodology for each was not frequently reported in study records. Most of the reported characterization relied on bulk characterization of EV isolates, with only 11% utilizing EV subpopulations in their experimental design. While this may be connected to a lack of available techniques suitable for clinical implementation, it also highlights the opportunity for use of EV subpopulations to improve translational efforts. As academic research identifies more chemically distinct subpopulations and technologies for their enrichment, we forecast to more refined EV trials in the near future. This review emphasizes the need for meticulous methodological reporting and consideration of EV subpopulations to enhance the translational success of EV-based interventions, pointing towards a paradigm shift in personalized medicine.

Keywords: diagnostics; drug delivery vehicles; exosomes; heterogeneity; therapeutics.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Flow diagram of the study inclusion and exclusion.
FIGURE 2
FIGURE 2
Total EV‐related clinical trial description. A timeline of study record posting dates (a) and study type (b) for EV‐related clinical trials identified via ClinicalTrials.gov shows an exponential rise in EV‐related clinical trials the majority of which are for diagnostics.
FIGURE 3
FIGURE 3
Summary of EV‐related diagnostic and companion diagnostic clinical trials. (a, e) Number of trials posted by year shows most diagnostic trials were posted in the late 2010s and early 2020s and the majority are EV focused. Most frequent conditions (≥5 trials) (b, f), general indication category (c, g) show that the majority of trials focus on various cancers. For both trial types, the majority of studies utilized blood or blood derivatives as an EV source (d, h).
FIGURE 4
FIGURE 4
Summary of EV‐related therapeutic clinical trials. (a) All EV‐related therapeutic trials were posted since 2010, and the majority are focused on EVs. Most frequent condition (≥3 trials) (b), indication category (c), EV source, (d) MSC source (for trials utilizing MSC‐EVs), and route of administration were tabulated showing a large proportion of therapeutics intended for respiratory illnesses and largely being sources from MSCs.
FIGURE 5
FIGURE 5
Summary of engineered EVs in EV‐related therapeutic trials. The proportion of trials utilizing engineered EVs (a) and the approach to EV engineering were tabulated (b).
FIGURE 6
FIGURE 6
Summary of EV isolation methods in EV‐related clinical trials. Total study records identifying isolation method (a), and the frequency of specification by trial type (b) were quantified. The total number of isolation methods used per study were also quantified (c). Isolation method was determined as a percentage of all isolation methods identified (not as percentage of trials) (d).
FIGURE 7
FIGURE 7
Summary of EV characterization methods in EV‐related clinical trials. Study records identifying any characterization methods (a) and total number of characterization techniques identified (c) were tabulated showing that characterization method was overwhelmingly unreported. Most commonly identified characterization techniques were identified across all trial (≥8 trials) and shown in (a). In addition, characterization techniques were categorized to determine the readout and tabulated to show trends in molecules and characteristics of interest (e).
FIGURE 8
FIGURE 8
Summary of EV subpopulation uses in clinical trials. Fractions of study records identifying use of or attention to an EV subpopulation (a) and the number of each of these trials per year (b). These trials were broken down to show the frequency of subpopulation consideration in each trial type (c) and by subpopulation parameter (d) with a majority focusing on cell source subpopulations.
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