Clinical-grade extracellular vesicles derived from umbilical cord mesenchymal stromal cells: preclinical development and first-in-human intra-articular validation as therapeutics for knee osteoarthritis

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dc.coverageDOI: 10.1186/s12951-024-03088-x
dc.creatorFigueroa-Valdés, Aliosha I.
dc.creatorLuz-Crawford, Patricia
dc.creatorHerrera-Luna, Yeimi
dc.creatorGeorges-Calderón, Nicolás
dc.creatorGarcía, Cynthia
dc.creatorTobar, Hugo E.
dc.creatorAraya, María Jesús
dc.creatorMatas, José
dc.creatorDonoso-Meneses, Darío
dc.creatorde la Fuente, Catalina
dc.creatorCuenca, Jimena
dc.creatorParra, Eliseo
dc.creatorLillo, Fernando
dc.creatorVarela, Cristóbal
dc.creatorCádiz, María Ignacia
dc.creatorVernal, Rolando
dc.creatorOrtloff, Alexander
dc.creatorNardocci, Gino
dc.creatorCastañeda, Verónica
dc.creatorAdasme-Vidal, Catalina
dc.creatorKunze-Küllmer, Maximiliano
dc.creatorHidalgo, Yessia
dc.creatorEspinoza, Francisco
dc.creatorKhoury, Maroun
dc.creatorAlcayaga-Miranda, Francisca
dc.date2025
dc.date.accessioned2025-11-18T19:55:48Z
dc.date.available2025-11-18T19:55:48Z
dc.description<p>Osteoarthritis (OA) is a joint disease characterized by articular cartilage degradation. Persistent low-grade inflammation defines OA pathogenesis, with crucial involvement of pro-inflammatory M1-like macrophages. While mesenchymal stromal cells (MSC) and their small extracellular vesicles (sEV) hold promise for OA treatment, achieving consistent clinical-grade sEV products remains a significant challenge. This study aims to develop fully characterized, reproducible, clinical-grade batches of sEV derived from umbilical cord (UC)-MSC for the treatment of OA while assessing its efficacy and safety. Initially, a standardized, research-grade manufacturing protocol was established to ensure consistent sEV production. UC-MSC-sEV characterization under non-cGMP conditions showed consistent miRNA and protein profiles, suggesting their potential for standardized manufacturing. In vitro studies evaluated the efficacy, safety, and potency of sEV; animal studies confirmed their effectiveness and safety. In vitro, UC-MSC-sEV polarized macrophages to an anti-inflammatory M2b-like phenotype, through STAT1 modulation, indicating their potential to create an anti-inflammatory environment in the affected joints. In silico studies confirmed sEV's immunosuppressive signature through miRNA and proteome analysis. In an OA mouse model, sEV injected intra-articularly (IA) induced hyaline cartilage regeneration, validated by histological and μCT analyses. The unique detection of sEV signals within the knee joint over time highlights its safety profile by confirming the retention of sEV in the joint. The product development of UC-MSC-sEV involved refining, standardizing, and validating processes in compliance with GMP standards. The initial assessment of the safety of the clinical-grade product via IA administration in a first-in-human study showed no adverse effects after a 12 month follow-up period. These results support the progress of this sEV-based therapy in an early-phase clinical trial, the details of which are presented and discussed in this work. This study provides data on using UC-MSC-sEV as local therapy for OA, highlighting their regenerative and anti-inflammatory properties and safety in preclinical and a proof-of-principle clinical application.</p>eng
dc.identifierhttps://investigadores.uandes.cl/en/publications/813ac9c7-f93b-419c-a880-da37f6d446b4
dc.identifier.urihttps://repositorio.uandes.cl/handle/uandes/59455
dc.languageeng
dc.rightsinfo:eu-repo/semantics/openAccess
dc.sourcevol.23 (2025) nr.1
dc.subjectExosomes
dc.subjectFirst-in-human
dc.subjectMacrophage polarization
dc.subjectManufacturing
dc.subjectMesenchymal
dc.subjectOsteoarthritis
dc.subjectSmall extracellular vesicles
dc.subjectStem cells
dc.subjectStromal cells
dc.subjectSDG 3 - Good Health and Well-being
dc.titleClinical-grade extracellular vesicles derived from umbilical cord mesenchymal stromal cells: preclinical development and first-in-human intra-articular validation as therapeutics for knee osteoarthritiseng
dc.typeArticleeng
dc.typeArtículospa
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