Intra‐articular injection of mesenchymal stem cells expressing coagulation factor ameliorates hemophilic arthropathy in factor VIII‐deficient mice

Abstract

Summary. Background: Transplantation of cells overexpressing a target protein represents a viable gene therapeutic approach for treating hemophilia. Here, we focused on the use of autologous mesenchymal stem cells (MSCs) expressing coagulation factor for the treatment of coagulation factor VIII (FVIII) deficiency in mice. Methods and Results: Analysis of luciferase gene constructs driven by different promoters revealed that the plasminogen activator inhibitor‐1 (PAI‐1) gene promoter coupled with the cytomegalovirus promoter enhancer region was one of the most effective promoters for producing the target protein. MSCs transduced with the simian immunodeficiency virus (SIV) vector containing the FVIII gene driven by the PAI‐1 promoter expressed FVIII for several months, and this expression was maintained after multiple mesenchymal lineage differentiation. Although intravenous injection of cell supernatant derived from MSCs transduced with an SIV vector containing the FVIII gene driven by the PAI‐1 promoter significantly increased plasma FVIII levels, subcutaneous implantation of the MSCs resulted in a transient and weak increase in plasma FVIII levels in FVIII‐deficient mice. Interestingly, intra‐articular injection of the transduced MSCs significantly ameliorated the hemarthrosis and hemophilic arthropathy induced by knee joint needle puncture in FVIII‐deficient mice. The therapeutic effects of a single intra‐articular injection of transduced MSCs to inhibit joint bleeding persisted for at least 8 weeks after administration. Conclusions: MSCs provide a promising autologous cell source for the production of coagulation factor. Intra‐articular injection of MSCs expressing coagulation factor may offer an attractive treatment approach for hemophilic arthropathy.

Gene therapy for hemophilia

“…In mice, MSCs transduced via LV to express F.VIII were not able to mediate systemic correction; however, following intra-articular injection, they were able to reduce bleeding following joint capsular needle puncture injury (323). When LV-transduced MSCs were injected intraperitoneally into hemophilic sheep, however, they demonstrated widespread engraftment in organs and joints and were able to prevent further spontaneous bleeding as well as resolving pre-existing joint damage (324).…”

Experimental study on the role of intra‐articular injection of MSCs on cartilage regeneration in haemophilia

“…Kashiwakura et al perfectly investigated the effects of the transduced MSCs containing the F-VIII gene by Valentino et al quantitative grading system of synovitis with only one score relating to cartilage erosion [20,38]. Kashiwakura et al perfectly investigated the effects of the transduced MSCs containing the F-VIII gene by Valentino et al quantitative grading system of synovitis with only one score relating to cartilage erosion [20,38].…”

“…The ectopically implantation of ex vivo transduced F-IX or F-VIII genes either with adeno-associated virus or MSCs transduced by simian immunodeficiency virus vectors have performed after a single joint bleed as a novel therapeutic approach to prevent haemophilic synovitis [20,21]. Moreover, feasibility of autologous BM-derived MSCs for haemophilic arthropathy was investigated by morphology and flow cytometric analysis and showed BM-derived MSCs of three PWH were capable of differentiating into chondrocytes, similarly to those in a healthy adult [22].…”

Haemophilic arthropathy: A narrative review on the use of intra‐articular drugs for arthritis

“…35 Regarding haemophilic arthropathy, a 2016 review promoted the future use of MSCs in humans although it only involved experimental studies, making the issue about the efficacy of MSC in human HA still premature. 18,19 Future studies that analyse the efficacy and safety of MSC in patients with HA are necessary. 18,19 Future studies that analyse the efficacy and safety of MSC in patients with HA are necessary.…”

“…The main outcome of a single intra-articular injection of MSCc in the mice's knee was the inhibition of joint bleeding that persisted for 8 weeks after treatment evaluated with histopathologic images 18. The first article ofKashiwakura et al analysed the intra-articular injection of MSCs in a group of mice induced to have a deficient factor VIII through the use of a lentiviral vector plasmid.…”