Invossa™ (TISSUEGENE-C) induces an anti-inflammatory environment in the arthritic knee joints via macrophage polarization

      Purpose: INVOSSA™ (TissueGene-C) is a novel cell and gene therapy for osteoarthritis (OA). The phase III clinical study has been completed and its outcome showed that INVOSSA™ improved pain, daily activities, sports functions and cartilage structure in patients with OA. Here we hypothesized that treatment of INVOSSA™ may induce an anti-inflammatory environment, especially M2 macrophage differentiation, which contributes to the reduction of the pain and cartilage regeneration. In this study, we evaluated the effect of INVOSSA™ on pain and structural improvements with its anti-inflammatory modulations in the arthritic knee joints of a rodent OA model.
      Methods: The in vivo efficacy of INVOSSA™ or each component of INVOSSA™ and a vehicle control (CS-10) were analyzed in a rat MIA model. Pain behavior was assessed by von Frey filament test, and cartilage regeneration was analyzed by various histological stainings. To evaluate the anti-inflammatory effect of INVOSSA™, various cytokines were analyzed by a multiplex assay using synovial fluid. The synovial macrophage differentiation profiles were investigated by immunohistochemistry with CD86 as M1 marker and Arginase 1 as M2 marker. Gene expression profiles were analyzed by quantitative RT-PCR.
      Results: Pain relief was shown initially at day 15 and maintained up to 56 days post INVOSSA™ treatment. The regenerated cartilage showed hyaline cartilage characteristics post INVOSSA™ treatment. Cytokine expression profiles in synovial fluid showed that INVOSSA™ induced IL-10, which was consistent to the observation of CD68-positive monocyte infiltration to the synovial membrane. Furthermore, the INVOSSA™ attracted more arginase 1-positive cells to the synovial membrane. However, the number of CD86-positive cells post INVOSSA™ treatment was comparable to the control treatment. Quantitative RT-PCR analysis also showed that M2 macrophage related markers were highly up-regulated in the synovial membranes in INVOSSA™ treated group.
      Conclusions: This study supports that INVOSSA™ holds a great potential for a disease modifying osteoarthritis drug.