Sustained fetal hemoglobin induction in vivo is achieved by <i>BCL11A</i> interference and coexpressed truncated erythropoietin receptor
Naoya Uchida, Francesca Ferrara, Claire Drysdale, Morgan Yapundich, Jackson Gamer, Tina Nassehi, Julia DiNicola, Yoshitaka SHIBATA, Matthew M. Wielgosz, Yoon‐Sang Kim, Matthew Bauler, Robert E. Throm, Juan J. Haro‐Mora, Selami Demirci, Aylin Bonifacino, Allen E. Krouse, Nathaniel S. Linde, Robert E. Donahue, Byoung Y. Ryu, John F. Tisdale
Abstract
cells with erythroid-specific expression of both thEpoR and shmiR BCL11A and compared to cells modified with shmiR BCL11A only. We found that thEpoR enhanced shmiR BCL11A-based fetal hemoglobin (HbF) induction in both xenograft mice and rhesus macaques, whereas HbF induction with shmiR BCL11A only was robust, yet transient. thEpoR/shmiR BCL11A coexpression allowed for sustained HbF induction at 20 to 25% in rhesus macaques for 4 to 8 months. In summary, we developed erythroid-specific thEpoR/shmiR BCL11A-expressing vectors, enhancing HbF induction in xenograft mice and rhesus macaques. The sustained HbF induction achieved by addition of thEpoR and shmiR BCL11A may represent a viable gene therapy strategy for hemoglobin disorders.