Base editing of haematopoietic stem cells rescues sickle cell disease in mice

Gregory A. Newby, Jonathan S. Yen (), Kaitly J. Woodard, Thiyagaraj Mayuranathan, Cicera R. Lazzarotto, Yichao Li, Heather Sheppard-Tillman, Shaina N. Porter, Yu Yao, Kalin Mayberry, Kelcee A. Everette, Yoonjeong Jang, Christopher J. Podracky, Elizabeth Thaman, Christophe Lechauve, Akshay Sharma, Jordana M. Henderson, Michelle F. Richter, Kevin T. Zhao, Shannon M. Miller, Tina Wang, Luke W. Koblan, Anton P. McCaffrey, John F. Tisdale, Theodosia A. Kalfa, Shondra M. Pruett-Miller, Shengdar Q. Tsai, Mitchell J. Weiss () and David R. Liu ()
Additional contact information
Gregory A. Newby: Broad Institute of Harvard and MIT
Jonathan S. Yen: St. Jude Children’s Research Hospital
Kaitly J. Woodard: St. Jude Children’s Research Hospital
Thiyagaraj Mayuranathan: St. Jude Children’s Research Hospital
Cicera R. Lazzarotto: St. Jude Children’s Research Hospital
Yichao Li: St. Jude Children’s Research Hospital
Heather Sheppard-Tillman: St. Jude Children’s Research Hospital
Shaina N. Porter: St. Jude Children’s Research Hospital
Yu Yao: St. Jude Children’s Research Hospital
Kalin Mayberry: St. Jude Children’s Research Hospital
Kelcee A. Everette: Broad Institute of Harvard and MIT
Yoonjeong Jang: St. Jude Children’s Research Hospital
Christopher J. Podracky: Broad Institute of Harvard and MIT
Elizabeth Thaman: Cincinnati Children’s Hospital Medical Center
Christophe Lechauve: St. Jude Children’s Research Hospital
Akshay Sharma: St Jude Children’s Research Hospital
Jordana M. Henderson: TriLink BioTechnologies
Michelle F. Richter: Broad Institute of Harvard and MIT
Kevin T. Zhao: Broad Institute of Harvard and MIT
Shannon M. Miller: Broad Institute of Harvard and MIT
Tina Wang: Broad Institute of Harvard and MIT
Luke W. Koblan: Broad Institute of Harvard and MIT
Anton P. McCaffrey: TriLink BioTechnologies
John F. Tisdale: Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute and National Institute of Diabetes and Digestive and Kidney Diseases
Theodosia A. Kalfa: Cincinnati Children’s Hospital Medical Center
Shondra M. Pruett-Miller: St. Jude Children’s Research Hospital
Shengdar Q. Tsai: St. Jude Children’s Research Hospital
Mitchell J. Weiss: St. Jude Children’s Research Hospital
David R. Liu: Broad Institute of Harvard and MIT

Nature, 2021, vol. 595, issue 7866, 295-302

Abstract: Abstract Sickle cell disease (SCD) is caused by a mutation in the β-globin gene HBB1. We used a custom adenine base editor (ABE8e-NRCH)2,3 to convert the SCD allele (HBBS) into Makassar β-globin (HBBG), a non-pathogenic variant4,5. 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 HBBS to HBBG. Sixteen weeks after transplantation of edited human HSPCs into immunodeficient mice, the frequency of HBBG was 68% and hypoxia-induced sickling of bone marrow reticulocytes had decreased fivefold, indicating durable gene editing. To assess the physiological effects of HBBS base editing, we delivered ABE8e-NRCH and guide RNA into HSPCs from a humanized SCD mouse6 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 HBBS-to-HBBG 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 HBBS, generates benign HBBG, and minimizes the undesired consequences of double-strand DNA breaks.

Date: 2021
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DOI: 10.1038/s41586-021-03609-w

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