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
Abstract 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...
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2025-01-01
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| author | Aliosha I. Figueroa-Valdés Patricia Luz-Crawford Yeimi Herrera-Luna Nicolás Georges-Calderón Cynthia García Hugo E. Tobar María Jesús Araya José Matas Darío Donoso-Meneses Catalina de la Fuente Jimena Cuenca Eliseo Parra Fernando Lillo Cristóbal Varela María Ignacia Cádiz Rolando Vernal Alexander Ortloff Gino Nardocci Verónica Castañeda Catalina Adasme-Vidal Maximiliano Kunze-Küllmer Yessia Hidalgo Francisco Espinoza Maroun Khoury Francisca Alcayaga-Miranda |
| author_facet | Aliosha I. Figueroa-Valdés Patricia Luz-Crawford Yeimi Herrera-Luna Nicolás Georges-Calderón Cynthia García Hugo E. Tobar María Jesús Araya José Matas Darío Donoso-Meneses Catalina de la Fuente Jimena Cuenca Eliseo Parra Fernando Lillo Cristóbal Varela María Ignacia Cádiz Rolando Vernal Alexander Ortloff Gino Nardocci Verónica Castañeda Catalina Adasme-Vidal Maximiliano Kunze-Küllmer Yessia Hidalgo Francisco Espinoza Maroun Khoury Francisca Alcayaga-Miranda |
| author_sort | Aliosha I. Figueroa-Valdés |
| collection | DOAJ |
| description | Abstract 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. Graphical Abstract |
| format | Article |
| id | doaj-art-ef91378bc17e4e55a600a5674f2ac5af |
| institution | Kabale University |
| issn | 1477-3155 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
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| series | Journal of Nanobiotechnology |
| spelling | doaj-art-ef91378bc17e4e55a600a5674f2ac5af2025-01-19T12:37:50ZengBMCJournal of Nanobiotechnology1477-31552025-01-0123113210.1186/s12951-024-03088-xClinical-grade extracellular vesicles derived from umbilical cord mesenchymal stromal cells: preclinical development and first-in-human intra-articular validation as therapeutics for knee osteoarthritisAliosha I. Figueroa-Valdés0Patricia Luz-Crawford1Yeimi Herrera-Luna2Nicolás Georges-Calderón3Cynthia García4Hugo E. Tobar5María Jesús Araya6José Matas7Darío Donoso-Meneses8Catalina de la Fuente9Jimena Cuenca10Eliseo Parra11Fernando Lillo12Cristóbal Varela13María Ignacia Cádiz14Rolando Vernal15Alexander Ortloff16Gino Nardocci17Verónica Castañeda18Catalina Adasme-Vidal19Maximiliano Kunze-Küllmer20Yessia Hidalgo21Francisco Espinoza22Maroun Khoury23Francisca Alcayaga-Miranda24Laboratorio de Medicina Nano-Regenerativa, Centro de Investigación e Innovación Biomédica (CiiB), Universidad de los AndesLaboratorio de Inmunología Celular y Molecular, Centro de Investigación e Innovación Biomédica (CiiB), Universidad de los AndesLaboratorio de Inmunología Celular y Molecular, Centro de Investigación e Innovación Biomédica (CiiB), Universidad de los AndesLaboratorio de Medicina Nano-Regenerativa, Centro de Investigación e Innovación Biomédica (CiiB), Universidad de los AndesLaboratorio de Inmunología Celular y Molecular, Centro de Investigación e Innovación Biomédica (CiiB), Universidad de los AndesLaboratorio de Medicina Nano-Regenerativa, Centro de Investigación e Innovación Biomédica (CiiB), Universidad de los AndesLaboratorio de Inmunología Celular y Molecular, Centro de Investigación e Innovación Biomédica (CiiB), Universidad de los AndesCentro de Terapia Celular, Clínica Universidad de los AndesLaboratorio de Medicina Nano-Regenerativa, Centro de Investigación e Innovación Biomédica (CiiB), Universidad de los AndesConsorcio REGENERO, Chilean Consortium for Regenerative MedicineLaboratorio de Medicina Nano-Regenerativa, Centro de Investigación e Innovación Biomédica (CiiB), Universidad de los AndesConsorcio REGENERO, Chilean Consortium for Regenerative MedicineConsorcio REGENERO, Chilean Consortium for Regenerative MedicineDepartmento de Radiología, Clínica Universidad de los AndesLaboratorio de Medicina Nano-Regenerativa, Centro de Investigación e Innovación Biomédica (CiiB), Universidad de los AndesLaboratorio de Biología Periodontal, Facultad de Odontología, Universidad de ChileDepartamento de Ciencias Veterinarias y Salud Pública, Facultad de Recursos Naturales, Universidad Católica de TemucoLaboratorio de Biología Molecular y Bioinformática, Centro de Investigación e Innovación Biomédica (CiiB), Universidad de los AndesLaboratorio de Biología Molecular y Bioinformática, Centro de Investigación e Innovación Biomédica (CiiB), Universidad de los AndesLaboratorio de Medicina Nano-Regenerativa, Centro de Investigación e Innovación Biomédica (CiiB), Universidad de los AndesConsorcio REGENERO, Chilean Consortium for Regenerative MedicineLaboratorio de Medicina Nano-Regenerativa, Centro de Investigación e Innovación Biomédica (CiiB), Universidad de los AndesConsorcio REGENERO, Chilean Consortium for Regenerative MedicineLaboratorio de Medicina Nano-Regenerativa, Centro de Investigación e Innovación Biomédica (CiiB), Universidad de los AndesLaboratorio de Medicina Nano-Regenerativa, Centro de Investigación e Innovación Biomédica (CiiB), Universidad de los AndesAbstract 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. Graphical Abstracthttps://doi.org/10.1186/s12951-024-03088-xSmall extracellular vesiclesExosomesOsteoarthritisMesenchymalStem cellsStromal cells |
| spellingShingle | Aliosha I. Figueroa-Valdés Patricia Luz-Crawford Yeimi Herrera-Luna Nicolás Georges-Calderón Cynthia García Hugo E. Tobar María Jesús Araya José Matas Darío Donoso-Meneses Catalina de la Fuente Jimena Cuenca Eliseo Parra Fernando Lillo Cristóbal Varela María Ignacia Cádiz Rolando Vernal Alexander Ortloff Gino Nardocci Verónica Castañeda Catalina Adasme-Vidal Maximiliano Kunze-Küllmer Yessia Hidalgo Francisco Espinoza Maroun Khoury Francisca Alcayaga-Miranda 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 Journal of Nanobiotechnology Small extracellular vesicles Exosomes Osteoarthritis Mesenchymal Stem cells Stromal cells |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Small extracellular vesicles Exosomes Osteoarthritis Mesenchymal Stem cells Stromal cells |
| url | https://doi.org/10.1186/s12951-024-03088-x |
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