title: PEO-PPO-PEO Carriers for rAAV-Mediated Transduction of Human Articular Chondrocytes in Vitro and in a Human Osteochondral Defect Model.
abstract: Gene therapy is an attractive strategy for the durable treatment of human osteoarthritis (OA), a gradual, irreversible joint disease. Gene carriers based on the small human adeno-associated virus (AAV) exhibit major efficacy in modifying damaged human articular cartilage in situ over extended periods of time. Yet, clinical application of recombinant AAV (rAAV) vectors remains complicated by the presence of neutralizing antibodies against viral capsid elements in a majority of patients. The goal of this study was to evaluate the feasibility of delivering rAAV vectors to human OA chondrocytes in vitro and in an experimental model of osteochondral defect via polymeric micelles to protect gene transfer from experimental neutralization. Interaction of rAAV with micelles of linear (poloxamer PF68) or X-shaped (poloxamine T908) poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) copolymers (PEO-PPO-PEO micelles) was characterized by means of isothermal titration calorimetry. Micelle encapsulation allowed an increase in both the stability and bioactivity of rAAV vectors and promoted higher levels of safe transgene (lacZ) expression both in vitro and in experimental osteochondral defects compared with that of free vector treatment without detrimental effects on the biological activity of the cells or their phenotype. Remarkably, protection against antibody neutralization was also afforded when delivering rAAV via PEO-PPO-PEO micelles in all systems evaluated, especially when using T908. Altogether, these findings show the potential of PEO-PPO-PEO micelles as effective tools to improve current gene-based treatments for human OA.
authors.affiliation: Center of Experimental Orthopaedics, Saarland University Medical Center , Homburg, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Rey-Rico
authors.affiliation: Center of Experimental Orthopaedics, Saarland University Medical Center , Homburg, Germany.
authors.forename: Janina
authors.initials: J
authors.lastname: Frisch
authors.affiliation: Center of Experimental Orthopaedics, Saarland University Medical Center , Homburg, Germany.
authors.forename: Jagadesh Kumar
authors.initials: JK
authors.lastname: Venkatesan
authors.affiliation: Center of Experimental Orthopaedics, Saarland University Medical Center , Homburg, Germany.
authors.forename: Gertrud
authors.initials: G
authors.lastname: Schmitt
authors.affiliation: Departamento de Farmacia y Tecnología Farmacéutica, R+DPharma Group (GI-1645), Facultad de Farmacia, Universidade de Santiago de Compostela , Santiago de Compostela, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Rial-Hermida
authors.affiliation: Departamento de Física de la Materia Condensada, Facultad de Física, Universidade de Santiago de Compostela , Santiago de Compostela, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Taboada
authors.affiliation: Departamento de Farmacia y Tecnología Farmacéutica, R+DPharma Group (GI-1645), Facultad de Farmacia, Universidade de Santiago de Compostela , Santiago de Compostela, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Concheiro
authors.affiliation: Center of Experimental Orthopaedics, Saarland University Medical Center , Homburg, Germany.|Department of Orthopaedics and Orthopaedic Surgery, Saarland University Medical Center , Homburg, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Madry
authors.affiliation: Departamento de Farmacia y Tecnología Farmacéutica, R+DPharma Group (GI-1645), Facultad de Farmacia, Universidade de Santiago de Compostela , Santiago de Compostela, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Alvarez-Lorenzo
authors.affiliation: Center of Experimental Orthopaedics, Saarland University Medical Center , Homburg, Germany.
authors.forename: Magali
authors.initials: M
authors.lastname: Cucchiarini
mesh_terms: D002358:Cartilage, Articular; D019902:Chondrocytes; D000229:Dependovirus; D006801:Humans; D008823:Micelles; D011092:Polyethylene Glycols; D011409:Propylene Glycols
chemical_list: D008823:Micelles; C116176:PEO-PPO-PEO; D011409:Propylene Glycols; D011092:Polyethylene Glycols
keywords: human articular cartilage; micelles; osteoarthritis; poloxamers; poloxamines; rAAV gene transfer