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.

Significance: 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.

Trial registration: ClinicalTrials.gov NCT01585857.

Keywords: Adipose mesenchymal stromal cells; Intra-articular injection; Osteoarthritis; Phase I clinical trial; Regenerative medicine; Therapeutic potential.

Figure 1.

Flow chart of the clinical trial. Abbreviation: ASC, adipose-derived stromal cell.

Figure 2.

WOMAC pain and function improvement during the study. Abbreviation: WOMAC, Western Ontario and McMaster Universities Arthritis Index.

Figure 3.

dGEMRIC and T_1rho magnetic resonance imaging (MRI) of selected patients. The graphs on the left show the dGEMRIC (n = 6) and T_1rho (n = 5) values before and 4 months after cell therapy. Increasing dGEmRIC and decreasing T_1rho values are each known to correspond to increasing glycosaminoglycan/proteoglycan content and thus improved cartilage condition. On the right, the corresponding dGEMRIC and T_1rho maps are shown as a color-coded overlay on an anatomical MRI for a patient receiving a low cell dose. The observed values in the cartilage change in the time course can be easily seen and correspond to an increase in cartilage condition. Abbreviation: dGEMRIC, delayed gadolinium-enhanced magnetic resonance imaging of cartilage.

Figure 4.

Histologic findings. (A): Vascular congestion and weak lymphocytic infiltrate of the synovial (case 8) (magnification, ×50). (B): Osteoarthritic cartilage OARSI grade >3 (case 4) (×25). (C): Toluidine blue staining (case 2) (magnification, ×100). (D): Stem cell stroma shows an Alcian blue depleted matrix compared with the strong staining of osteoarthritic cartilage (case 2) (magnification, ×100). (E): Weak PS100 staining of possible stem cells on the cartilage surface and strong PS100 staining of chondrocytes (case 2) (magnification, ×100). Abbreviations: OARSI, Osteoarthritis Research Society International.