Effects of TGF-beta Overexpression via rAAV Gene Transfer on the Early Repair Processes in an Osteochondral Defect Model in Minipigs

Background: Application of the chondrogenic transforming growth factor beta (TGF-beta) is an attractive approach to enhance the intrinsic biological activities in damaged articular cartilage, especially when using direct gene transfer strategies based on the clinically relevant recombinant adeno-associated viral (rAAV) vectors. Purpose: To evaluate the ability of an rAAV-TGF-beta construct to modulate the early repair processes in sites of focal cartilage injury in minipigs in vivo relative to control (reporter lacZ gene) vector treatment. Study Design: Controlled laboratory study. Methods: Direct administration of the candidate rAAV-human TGF-beta (hTGF-beta) vector was performed in osteochondral defects created in the knee joint of adult minipigs for macroscopic, histological, immunohistochemical, histomorphometric, and micro-computed tomography analyses after 4 weeks relative to control (rAAV-lacZ) gene transfer. Results: Successful overexpression of TGF-beta via rAAV at this time point and in the conditions applied here triggered the cellular and metabolic activities within the lesions relative to lacZ gene transfer but, at the same time, led to a noticeable production of type I and X collagen without further buildup on the subchondral bone. Conclusion: Gene therapy via direct, local rAAV-hTGF-beta-injection stimulates the early reparative activities in focal cartilage lesions in vivo.