Four decades of adenovirus gene transfer vectors: History and current use.

Replication-deficient adenovirus-based gene therapy vectors were the first vectors demonstrated to mediate effective, robust in vivo gene transfer. The ease of genome engineering, large carrying capacity, and methods for large-scale vector production made adenoviral vectors a primary focus in the early days of gene therapy. Many vector modifications such as capsid engineering and regulated and cell-specific transgene expression were first demonstrated in adenovirus (Ad) vectors. However, early human studies proved disappointing, with safety and efficacy issues arising from anti-vector innate and acquired immune responses. While many gene therapy researchers moved to other vectors, others recognized that the immune response and limited duration of transgene expression were useful in the correct context. The striking example of this was the use of several effective adenovirus vectors engineered as COVID-19 vaccines estimated to have been administered to 2 billion people. In addition to vaccines, current applications of Ad vectors relate to anti-cancer therapies, tissue remodeling, and gene editing.