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Newby, Gregory A; Yen, Jonathan S; Woodard, Kaitly J; Mayuranathan, Thiyagaraj; Lazzarotto, Cicera R; Li, Yichao; Sheppard-Tillman, Heather; Porter, Shaina N; Yao, Yu; Mayberry, Kalin; Everette, Kelcee A; Jang, Yoonjeong; Podracky, Christopher J; Thaman, Elizabeth; Lechauve, Christophe; Sharma, Akshay; Henderson, Jordana M; Richter, Michelle F; Zhao, Kevin T; Miller, Shannon M; Wang, Tina; Koblan, Luke W; McCaffrey, Anton P; Tisdale, John F; Kalfa, Theodosia A; Pruett-Miller, Shondra M; Tsai, Shengdar Q; Weiss, Mitchell J; Liu, David R
Nature (London), 07/2021, Letnik: 595, Številka: 7866Journal Article
Sickle cell disease (SCD) is caused by a mutation in the β-globin gene HBB . We used a custom adenine base editor (ABE8e-NRCH) to convert the SCD allele (HBB ) into Makassar β-globin (HBB ), a non-pathogenic variant . Ex vivo delivery of mRNA encoding the base editor with a targeting guide RNA into haematopoietic stem and progenitor cells (HSPCs) from patients with SCD resulted in 80% conversion of HBB to HBB . Sixteen weeks after transplantation of edited human HSPCs into immunodeficient mice, the frequency of HBB was 68% and hypoxia-induced sickling of bone marrow reticulocytes had decreased fivefold, indicating durable gene editing. To assess the physiological effects of HBB base editing, we delivered ABE8e-NRCH and guide RNA into HSPCs from a humanized SCD mouse and then transplanted these cells into irradiated mice. After sixteen weeks, Makassar β-globin represented 79% of β-globin protein in blood, and hypoxia-induced sickling was reduced threefold. Mice that received base-edited HSPCs showed near-normal haematological parameters and reduced splenic pathology compared to mice that received unedited cells. Secondary transplantation of edited bone marrow confirmed that the gene editing was durable in long-term haematopoietic stem cells and showed that HBB -to-HBB editing of 20% or more is sufficient for phenotypic rescue. Base editing of human HSPCs avoided the p53 activation and larger deletions that have been observed following Cas9 nuclease treatment. These findings point towards a one-time autologous treatment for SCD that eliminates pathogenic HBB , generates benign HBB , and minimizes the undesired consequences of double-strand DNA breaks.
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