title: Adipose Mesenchymal Stromal Cell-Based Therapy for Severe Osteoarthritis of the Knee: A Phase I Dose-Escalation Trial.
abstract: : Osteoarthritis (OA) is the most widespread musculoskeletal disorder in adults. It leads to cartilage damage associated with subchondral bone changes and synovial inflammation, causing pain and disability. The present study aimed at evaluating the safety of a dose-escalation protocol of intra-articular injected adipose-derived stromal cells (ASCs) in patients with knee OA, as well as clinical efficacy as secondary endpoint. A bicentric, uncontrolled, open phase I clinical trial was conducted in France and Germany with regulatory agency approval for ASC expansion procedure in both countries. From April 2012 to December 2013, 18 consecutive patients with symptomatic and severe knee OA were treated with a single intra-articular injection of autologous ASCs. The study design consisted of three consecutive cohorts (six patients each) with dose escalation: low dose (2 × 10(6) cells), medium dose (10 × 10(6)), and high dose (50 × 10(6)). The primary outcome parameter was safety evaluated by recording adverse events throughout the trial, and secondary parameters were pain and function subscales of the Western Ontario and McMaster Universities Arthritis Index. After 6 months of follow-up, the procedure was found to be safe, and no serious adverse events were reported. Four patients experienced transient knee joint pain and swelling after local injection. Interestingly, patients treated with low-dose ASCs experienced significant improvements in pain levels and function compared with baseline. Our data suggest that the intra-articular injection of ASCs is a safe therapeutic alternative to treat severe knee OA patients. A placebo-controlled double-blind phase IIb study is being initiated to assess clinical and structural efficacy.
  
  
  CONCLUSIONS
  Although this phase I study included a limited number of patients without a placebo arm, it showed that local injection of autologous adipose-derived stem cells was safe and well tolerated in patients with knee osteoarthritis. This study also provides encouraging preliminary evidence of efficacy. Larger and controlled long-term studies are now mandatory to confirm whether this new strategy of cell therapy can improve pain and induce structural benefit in osteoarthritis.
authors.affiliation: Clinical Immunology and Osteoarticular Diseases Therapeutic Unit, Lapeyronie University Hospital, Montpellier, France INSERM, U1183, Saint-Eloi Hospital, Montpellier, France.
authors.forename: Yves-Marie
authors.initials: YM
authors.lastname: Pers
authors.affiliation: Department of Orthopaedic Surgery, König-Ludwig-Haus, University of Würzburg, Würzburg, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Rackwitz
authors.affiliation: Clinical Immunology and Osteoarticular Diseases Therapeutic Unit, Lapeyronie University Hospital, Montpellier, France.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Ferreira
authors.affiliation: Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB, Translational Center "Regenerative Therapies for Oncology and Musculoskeletal Diseases," Würzburg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Pullig
authors.affiliation: Department for Cell and Tissue Pathobiology of Tumor, Hospital Saint Eloi, Montpellier, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Delfour
authors.affiliation: Regenerative Medicine Institute, Galway University, Galway, Ireland.
authors.forename: Frank
authors.initials: F
authors.lastname: Barry
authors.affiliation: Etablissement Français du Sang, Toulouse, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Sensebe
authors.affiliation: INSERM U1031 STROMAlab, Toulouse, France CNRS, Université Toulouse III, UPS UMR5273 F-31 432 STROMAlab, Toulouse, France.
authors.forename: Louis
authors.initials: L
authors.lastname: Casteilla
authors.affiliation: Etablissement Français du Sang, Toulouse, France INSERM U1031 STROMAlab, Toulouse, France CNRS, Université Toulouse III, UPS UMR5273 F-31 432 STROMAlab, Toulouse, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Fleury
authors.affiliation: Etablissement Français du Sang, Toulouse, France Univercell Biosolutions, Toulouse, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bourin
authors.affiliation: INSERM, U1183, Saint-Eloi Hospital, Montpellier, France.
authors.forename: Danièle
authors.initials: D
authors.lastname: Noël
authors.affiliation: Department of Orthopaedic Surgery, Lapeyronie University Hospital, Montpellier, France.
authors.forename: François
authors.initials: F
authors.lastname: Canovas
authors.affiliation: Department of Radiology, Lapeyronie Hospital, Montpellier, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Cyteval
authors.affiliation: Laboratory of Immunorheumatology and Tissue Regeneration, Istituto Ortopedico Rizzoli, Bologna, Italy.
authors.forename: Gina
authors.initials: G
authors.lastname: Lisignoli
authors.affiliation: MRB Research Center Magnetic Resonance Bavaria, Würzburg, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Schrauth
authors.affiliation: MRB Research Center Magnetic Resonance Bavaria, Würzburg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Haddad
authors.affiliation: Maxillofacial, Plastic Reconstructive, and Aesthetic Surgery Department, Gui de Chauliac Hospital, Montpellier, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Domergue
authors.affiliation: Department of Orthopaedic Surgery, König-Ludwig-Haus, University of Würzburg, Würzburg, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Noeth
authors.affiliation: Clinical Immunology and Osteoarticular Diseases Therapeutic Unit, Lapeyronie University Hospital, Montpellier, France INSERM, U1183, Saint-Eloi Hospital, Montpellier, France christian.jorgensen@inserm.fr.
authors.forename: Christian
authors.initials: C
authors.lastname: Jorgensen
mesh_terms: D000273:Adipose Tissue / Q000166:cytology* / Q000637:transplantation; D000368:Aged; D002452:Cell Count; D005260:Female; D006801:Humans; D007270:Injections, Intra-Articular; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000473:pathology / Q000628:therapy*; D012720:Severity of Illness Index; D016896:Treatment Outcome
keywords: Adipose mesenchymal stromal cells; Intra-articular injection; Osteoarthritis; Phase I clinical trial; Regenerative medicine; Therapeutic potential