Inherent hepatocytic heterogeneity determines expression and retention of edited F9 alleles post-AAV/CRISPR infusion

• DOI: 10.1073/pnas.2110887118
• Publication Date: 2021-10-14T22:00:46Z
• Authors: Qiang Wang; Lin Zhang; Guo-Wei Zhang; Jian-Hua Mao; Xiao-Dong Xi; Lu Jiang; Gang Lv; Jing Lu; Yan Shen; Zhu Chen; Jiang Zhu; Sai-Juan Chen
• Keywords: Factor IX; Trans-activating crRNA

Significance Application scope, underlying mechanisms, and potential limitation of AAV/CRISPR-mediated hepatic gene editing remain unexplored. Here we report that a synthetic enhancer/promoter (P2) incorporation empowered AAV/CRISPR to restore FIX-encoding capacity severe F9 defect involving the regulatory region. Systemic analyses revealed critical role host cell heterogenicity in determining therapeutic benefit this regimen, wherein subclinical inflammation posttreatment regulated P2 activity retention edited alleles hepatocytic subset–dependent manner. Moreover, preeminent presence hematopoietic cells implicated their involvement fueling restricting inflammation. Collectively, these results characterize factors efficacy durability AAV/CRIPSR-mediated dealing with complicated monogenic disorders.