The functionality and efficiency of our strategy for PUMA gene delivery by an HAdV5-PUMA vector was demonstrated in vitro as well as in vivo in a rat AIA model. Gene transfer of PUMA into FLSs by BVCARHAdV5-PUMA, results in a rapid and massive cell death of FLS in vitro. In the context of chronic joint inflammation, the persistence of the disease results in part from the reduced sensitivity of FLS to death signals19. We also show that the FLS death cell induced by the HAdV5-PUMA vector is not inhibited in the presence of inflammatory cytokines. Using the rat AIA model, a single intra-articular injection of BVCARHAdV5-PUMA decreases significantly joint inflammation and improves joint function, resulting in minimal joint damage and bone loss. The two videos (Supplementary Movies 1 and 2) show that the treatment not only restores the joint functions and ambulation but also the mannerisms of the treated animal. The HAdV5-PUMA vector remains detectable in the injected joints 21 days post treatment, suggesting that the PUMA therapeutic effect can prolong in the joints beyond the observation period. The induction of antibodies against the adenovirus vector and its effect on the efficacy of intra-articulation treatment in humans is unknown. However, the possible adverse effects should be limited if a single therapeutic administration is proposed. Alternatively, chimeric adenovirus vectors with capsid proteins from other serotypes could replace the conventional HAdV5 vector to escape the circulating and local adenovirus neutralizing antibodies.