February 14th, 2021 - February 14, 2021—An editorial published in Blood by Lindsey A. George, M.D. (Children’s Hospital of Philadelphia) entitled No CpGs for AAVs? comments on the human clinical trial, NCT01687608, which explored a self-complementing optimized AAV vector to deliver the human FIX-Padua gene (Konkle et al., 2019). The treatment, BAX335, also known as AskBio009, employed an increased number of CpG di-nucleotides (ie. from 19 to 99) in the FIX open reading frame. Ultimately, the results of the clinical trial confirmed that long-term transgene expression was not achieved with AAV vectors having increased CpG content in the coding sequence for the transgene despite steroid intervention due to the innate immune stimulatory effect of CpG motifs enriched within their vector cassette.