Adeno-associated virus(AAV)is a promising viral vector and meets most requirements of being a safe biological agent.However,the commercialization of AAV has been hampered due to the limitation of large-scale production,and only a small number of clinical trials have been launched.In recent years,progresses in scalable manufacturing of AAV have dramatically improved AAVbased clinical researches,and have assisted the development of investigational drug products.An AAV1-based investigational product,Glybera,has been formally approved by European Commission for the treatment of lipoprotein lipase deficiency(LPLD).Glybera was the first gene therapy product in the western world,and the production process involves a scalable baculovirus-insect cell system.However,many problems still need to be solved to improve the productivity and quality of AAV.The present review gives critical insights into current state-of-the-art scalable producing methodologies of AAV,such as baculovirus-insect cell system,HSV complementation system,and Ad complementation system,along with a discussion on the problems,solutions,and developmental trends.Novel AAV-producing platforms in Saccharomyces cerevisiae and vaccinia virus complementation system will also be discussed.
