Cellular pathways of recombinant adeno-associated virus production for gene therapy

• Published in: Biotechnology advances 2021-07, Vol.49, p.107764-107764, Article 107764
• Main Authors: Sha, Sha, Maloney, Andrew J., Katsikis, Georgios, Nguyen, Tam N.T., Neufeld, Caleb, Wolfrum, Jacqueline, Barone, Paul W., Springs, Stacy L., Manalis, Scott R., Sinskey, Anthony J., Braatz, Richard D.
• Format: Article
• Language: English
• Subjects: AAV; Adeno-associated virus; Cellular pathways; Gene therapy; Gene therapy manufacturing; Mechanistic understanding; Production methods; Productivity; rAAV-based gene therapy; Recombinant AAV; Viral vectors; Wild-type AAV
• ISSN: 0734-9750; 1873-1899
• DOI: 10.1016/j.biotechadv.2021.107764

Recombinant adeno-associated viruses (rAAVs) are among the most important vectors for in vivo gene therapies. With the rapid development of gene therapy, current rAAV manufacturing capacity faces a challenge to meet the emerging demand for these therapies in the future. To examine the bottlenecks in rAAV production during cell culture, we focus here on an analysis of cellular pathways of rAAV production, based on an overview of assembly mechanisms first in the wild-type (wt) AAV replication and then in the common methods of rAAV production. The differences analyzed between the wild-type and recombinant systems provide insights into the mechanistic differences that may correlate with viral productivity. Based on these analyses, we identify potential barriers to high productivity of rAAV and discuss future directions for improvement to meet the emerging needs set by the growth of rAAV-based therapy and the needs of patients. •Recombinant AAV production methods are discussed and their cellular pathways are analyzed.•Differences between rAAV production and wtAAV replication systems are discussed.•The comparisons provide insights into improving rAAV production efficiency.•rAAV production improvements using molecular and process approaches are described.