Initial phase I safety of retrovirally transduced human chondrocytes expressing transforming growth factor-beta-1 in degenerative arthritis patients

Abstract

Background aims. TissueGene-C (TG-C) represents a cell-mediated gene therapy for localized delivery of allogeneic chondrocytes expressing transforming growth factor (TGF)-β1 directly to the damaged knee joint. Untransduced human chondrocytes (hChonJ cells) have also been incorporated into the TG-C product at a 3:1 ratio with TGF-β1-expressing chondrocytes (hChonJb#7) in order to help fill in the defect and as target cells for the actions of the expressed TGF-β1.Methods.A phase I dose-escalating clinical trial was performed to evaluate the safety and biologic activity of TG-C in patients with advanced osteoarthritis of the knee joint (full thickness cartilage defect) that was refractory to existing non-operative therapies. Following a single intra-articular injection into the joint space of the damaged knee, patients were monitored for safety, and an evaluation was performed to assess the pharmacokinetics and biologic activity of TG-C.Results.There were no treatment-related serious adverse events. Swelling, effusion and minor localized reactions such as warming sensation or itching were observed in a dose-dependent manner at the injection site. Knee evaluation scores seemed to indicate a dose-dependent trend toward efficacy; however, patient numbers were not sufficient to determine statistical significance.Conclusions.Overall, there were no significant safety issues related to the administration of TG-C, with only some minor injection site reactions observed. Additionally, knee scoring analyzes indicated a possibility that TG-C may contribute to improvement of arthritic symptoms. More study is warranted to evaluate further the safety and determine the potential efficacy of TG-C.

Gene therapy for chondral and osteochondral regeneration: is the future now?

“…The 2 chondrocytes fractions were administered together to provide elements critical to regenerate hyaline cartilage matrix, such as chondrocytes, TGF-β1 protein, type II collagen and glycosaminoglycans [81]. 6 of the 7 clinical trials on TG-C completed phase 1 or 2 evaluation on the safety and efficacy of the use of different modified chondrocytes concentrations in patients with grade IV degenerative arthritis of the knee joint (ICRS evaluation criteria from the MRI scan) with different lesion size: Starting from positive pre-clinical results on safety and efficacy (cartilage proliferation) [81], a phase I clinical trial performed in 12 patients (NCT00599248-2007) showed an improvement in knee OA symptoms and minimal adverse effects [94]. The results of one of the phase II clinical trials carried out on 102 patients (NCT01221441-2010) at 1 year follow-up, showed that TG-C had positive effects on pain levels determining a decrease of analgesics intake in treated patients compared to placebo [95].…”

Orthopedic cellular therapy: An overview with focus on clinical trials

“…The efficacy of cellular therapy can be augmented by combining it with multiple injections, arthroscopic injection and with minor surgery. A cell mediated gene therapy with irradiated TGFβ1 transfected chondrocytes and normal chondrocytes (Invossa TM ) was evaluated in a placebocontrolled, randomized clinical trial in patients with Kellgren and Lawrence grade Ⅲ OA of the knee with statistically significant improvement seen in pain (visual analog scale) and function (International Knee Documentation Committee subjective knee score) [56] .…”

Strategies for Improving the Repair of Focal Cartilage Defects

“…Indeed, it has been shown that transfected chondrocytes induced to express TGF-β1 enhance cartilage formation [109]. Nevertheless, no study has been performed to compare the efficacy between a scaffold-free approach and functionalized scaffolds.…”