# Extracellular Vesicles for Regenerative Medicine Applications
## 4 Clinical Development of EVs
### Future Challenges  
The translation of EV-based therapies has grown rapidly over the past two decades and has shown early potential for applications in TERM. However, there remain important challenges that must be addressed to facilitate the translation of these technologies into the clinic. These challenges primarily concern issues of large-scale production, understanding the biodistribution of EVs, and the absence of a thorough characterization of EVs to ensure safe and efficacious clinical translation. While the production of EVs shares similarities with the manufacturing of traditional biologic products (i.e., industrial production of antibodies and recombinant proteins), the optimal cell source and culture conditions for the large-scale production of EVs have not yet been established. MBVs are a potential solution to this limitation since they are isolated from readily available tissue. However, the preparation of MBVs also requires additional tissue decellularization and ECM solubilization steps that may affect their properties [74]. With regard to the collection, isolation, and purification of EV-based therapies, several studies have established a consensus that standardized protocols and outcome measurements are \begin{table}
\begin{tabular}{c c c c} \hline \hline
**NCT Number** & **Study Description** & **Status** & **Patients** \\ \hline NCT04544215 & \begin{tabular}{c} A clinical study of nebulized mesenchymal \\ progenitor cell exosomes for the treatment of \\ pulmonary infections \\ \end{tabular} & Recruiting & 60 \\ \hline NCT04213248 & \begin{tabular}{c} Assessment of the efficacy of UMSC-derived \\ exosomes on dry eye in patients with chronic Graft \\ Vs Host Disease (GVHD) \\ \end{tabular} & Recruiting & 27 \\ \hline NCT04602104 & \begin{tabular}{c} A clinical study of nebulized MSC-derived \\ exosomes for the treatment of ARDS \\ \end{tabular} & Recruiting & 169 \\ \hline NCT04388982 & \begin{tabular}{c} Evaluation of the safety and the efficacy of allogenic \\ adipose MSC-derived exosomes in patients with \\ Alzheimer’s disease \\ \end{tabular} & Recruiting & 9 \\ \hline \hline \end{tabular} \begin{tabular}{c} _Phase II_ \\ \hline NCT04969172 & \begin{tabular}{c} A phase II randomized, double-blind, \\ placebo-controlled study to evaluate the safety and \\ efficacy of exosomes overexpressing CD24 to \\ prevent clinical deterioration in patients with \\ moderate or severe COVID-19 infection \\ \end{tabular} & Active, not recruiting & 155 \\ \hline NCT04493242 & \begin{tabular}{c} Extracellular vesicle infusion treatment for \\ COVID-19-associated ARDS \\ \end{tabular} & Completed & 120 \\ \hline NCT03228277 & \begin{tabular}{c} Olmutinib trial in t/90m (+) non-small cell lung \\ cancer (NSCLC) patients detected by liquid biopsy \\ using bronchoalveolar lavage (BALF) extracellular \\ vesicular DNA \\ \end{tabular} & Completed & 25 \\ \hline NCT04602442 & \begin{tabular}{c} Assessment of the safety and efficacy of exosome \\ inhalation in COVID-19 associated pneumonia \\ \end{tabular} & Enrolling by invitation & 90 \\ \hline NCT05261360 & \begin{tabular}{c} Clinical efficacy of MSC-derived exosomes in \\ degenerative meniscal injury \\ \end{tabular} & Recruiting & 30 \\ \hline NCT04902183 & \begin{tabular}{c} Safety and efficacy of exosomes overexpressing \\ CD24 in two doses for patients with moderate or \\ severe COVID-19 \\ \end{tabular} & Recruiting & 90 \\ \hline \hline \end{tabular} \
\begin{tabular}{c} _Phase III_ \\ \hline NCT05216562 &
\begin{tabular}{c} Efficacy and safety of MSC-derived exosome therapy \\ to reduce hyper-inflammation in moderate \\ COVID-19 patients \\ \end{tabular} & Recruiting & 60 \\ \hline \hline \end{tabular}
\end{table} 
Table 2: Cont. necessary for large-scale translation [155; 156; 157; 158].