IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v595y2021i7866d10.1038_s41586-021-03609-w.html
   My bibliography  Save this article

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

Author

Listed:
  • Gregory A. Newby

    (Broad Institute of Harvard and MIT
    Harvard University
    Harvard University)

  • 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
    Harvard University
    Harvard University)

  • Yoonjeong Jang

    (St. Jude Children’s Research Hospital)

  • Christopher J. Podracky

    (Broad Institute of Harvard and MIT
    Harvard University
    Harvard University)

  • 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
    Harvard University
    Harvard University)

  • Kevin T. Zhao

    (Broad Institute of Harvard and MIT
    Harvard University
    Harvard University)

  • Shannon M. Miller

    (Broad Institute of Harvard and MIT
    Harvard University
    Harvard University)

  • Tina Wang

    (Broad Institute of Harvard and MIT
    Harvard University
    Harvard University)

  • Luke W. Koblan

    (Broad Institute of Harvard and MIT
    Harvard University
    Harvard University)

  • 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
    University of Cincinnati College of Medicine)

  • 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
    Harvard University
    Harvard University)

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.

Suggested Citation

  • 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. , 2021. "Base editing of haematopoietic stem cells rescues sickle cell disease in mice," Nature, Nature, vol. 595(7866), pages 295-302, July.
  • Handle: RePEc:nat:nature:v:595:y:2021:i:7866:d:10.1038_s41586-021-03609-w
    DOI: 10.1038/s41586-021-03609-w
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41586-021-03609-w
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.

    File URL: https://libkey.io/10.1038/s41586-021-03609-w?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Elliot H. Choi & Susie Suh & Andrzej T. Foik & Henri Leinonen & Gregory A. Newby & Xin D. Gao & Samagya Banskota & Thanh Hoang & Samuel W. Du & Zhiqian Dong & Aditya Raguram & Sajeev Kohli & Seth Blac, 2022. "In vivo base editing rescues cone photoreceptors in a mouse model of early-onset inherited retinal degeneration," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Mohsin Badat & Ayesha Ejaz & Peng Hua & Siobhan Rice & Weijiao Zhang & Lance D. Hentges & Christopher A. Fisher & Nicholas Denny & Ron Schwessinger & Nirmani Yasara & Noemi B. A. Roy & Fadi Issa & And, 2023. "Direct correction of haemoglobin E β-thalassaemia using base editors," Nature Communications, Nature, vol. 14(1), pages 1-7, December.
    3. Arianna Moiani & Gil Letort & Sabrina Lizot & Anne Chalumeau & Chloe Foray & Tristan Felix & Diane Clerre & Sonal Temburni-Blake & Patrick Hong & Sophie Leduc & Noemie Pinard & Alan Marechal & Eduardo, 2024. "Non-viral DNA delivery and TALEN editing correct the sickle cell mutation in hematopoietic stem cells," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    4. Panagiotis Antoniou & Giulia Hardouin & Pierre Martinucci & Giacomo Frati & Tristan Felix & Anne Chalumeau & Letizia Fontana & Jeanne Martin & Cecile Masson & Megane Brusson & Giulia Maule & Marion Ro, 2022. "Base-editing-mediated dissection of a γ-globin cis-regulatory element for the therapeutic reactivation of fetal hemoglobin expression," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    5. Jiaoyang Liao & Shuanghong Chen & Shenlin Hsiao & Yanhong Jiang & Yang Yang & Yuanjin Zhang & Xin Wang & Yongrong Lai & Daniel E. Bauer & Yuxuan Wu, 2023. "Therapeutic adenine base editing of human hematopoietic stem cells," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    6. Sebastian M. Siegner & Laura Ugalde & Alexandra Clemens & Laura Garcia-Garcia & Juan A. Bueren & Paula Rio & Mehmet E. Karasu & Jacob E. Corn, 2022. "Adenine base editing efficiently restores the function of Fanconi anemia hematopoietic stem and progenitor cells," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    7. Ju-Chan Park & Yun-Jeong Kim & Gue-Ho Hwang & Chan Young Kang & Sangsu Bae & Hyuk-Jin Cha, 2024. "Enhancing genome editing in hPSCs through dual inhibition of DNA damage response and repair pathways," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    8. Wei Qin & Fang Liang & Sheng-Jia Lin & Cassidy Petree & Kevin Huang & Yu Zhang & Lin Li & Pratishtha Varshney & Philippe Mourrain & Yanmei Liu & Gaurav K. Varshney, 2024. "ABE-ultramax for high-efficiency biallelic adenine base editing in zebrafish," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    9. Sundaram Acharya & Asgar Hussain Ansari & Prosad Kumar Das & Seiichi Hirano & Meghali Aich & Riya Rauthan & Sudipta Mahato & Savitri Maddileti & Sajal Sarkar & Manoj Kumar & Rhythm Phutela & Sneha Gul, 2024. "PAM-flexible Engineered FnCas9 variants for robust and ultra-precise genome editing and diagnostics," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    10. Zhenxing Yu & Zhike Lu & Jingjing Li & Yingying Wang & Panfeng Wu & Yini Li & Yangfan Zhou & Bailun Li & Heng Zhang & Yingzheng Liu & Lijia Ma, 2022. "PEAC-seq adopts Prime Editor to detect CRISPR off-target and DNA translocation," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    11. Jianli Tao & Qi Wang & Carlos Mendez-Dorantes & Kathleen H. Burns & Roberto Chiarle, 2022. "Frequency and mechanisms of LINE-1 retrotransposon insertions at CRISPR/Cas9 sites," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    12. Emily Zhang & Monica E. Neugebauer & Nicholas A. Krasnow & David R. Liu, 2024. "Phage-assisted evolution of highly active cytosine base editors with enhanced selectivity and minimal sequence context preference," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:595:y:2021:i:7866:d:10.1038_s41586-021-03609-w. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.