IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v589y2021i7843d10.1038_s41586-020-03086-7.html
   My bibliography  Save this article

In vivo base editing rescues Hutchinson–Gilford progeria syndrome in mice

Author

Listed:
  • Luke W. Koblan

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

  • Michael R. Erdos

    (National Institutes of Health)

  • Christopher Wilson

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

  • Wayne A. Cabral

    (National Institutes of Health)

  • Jonathan M. Levy

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

  • Zheng-Mei Xiong

    (National Institutes of Health)

  • Urraca L. Tavarez

    (National Institutes of Health)

  • Lindsay M. Davison

    (Vanderbilt University Medical Center)

  • Yantenew G. Gete

    (University of Maryland)

  • Xiaojing Mao

    (University of Maryland)

  • Gregory A. Newby

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

  • Sean P. Doherty

    (Vanderbilt University Medical Center)

  • Narisu Narisu

    (National Institutes of Health)

  • Quanhu Sheng

    (Vanderbilt University Medical Center)

  • Chad Krilow

    (National Institutes of Health)

  • Charles Y. Lin

    (Baylor College of Medicine
    Baylor College of Medicine
    Bio Inc.)

  • Leslie B. Gordon

    (Alpert Medical School of Brown University
    Harvard Medical School)

  • Kan Cao

    (University of Maryland)

  • Francis S. Collins

    (National Institutes of Health)

  • Jonathan D. Brown

    (Vanderbilt University Medical Center)

  • David R. Liu

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

Abstract

Hutchinson–Gilford progeria syndrome (HGPS or progeria) is typically caused by a dominant-negative C•G-to-T•A mutation (c.1824 C>T; p.G608G) in LMNA, the gene that encodes nuclear lamin A. This mutation causes RNA mis-splicing that produces progerin, a toxic protein that induces rapid ageing and shortens the lifespan of children with progeria to approximately 14 years1–4. Adenine base editors (ABEs) convert targeted A•T base pairs to G•C base pairs with minimal by-products and without requiring double-strand DNA breaks or donor DNA templates5,6. Here we describe the use of an ABE to directly correct the pathogenic HGPS mutation in cultured fibroblasts derived from children with progeria and in a mouse model of HGPS. Lentiviral delivery of the ABE to fibroblasts from children with HGPS resulted in 87–91% correction of the pathogenic allele, mitigation of RNA mis-splicing, reduced levels of progerin and correction of nuclear abnormalities. Unbiased off-target DNA and RNA editing analysis did not detect off-target editing in treated patient-derived fibroblasts. In transgenic mice that are homozygous for the human LMNA c.1824 C>T allele, a single retro-orbital injection of adeno-associated virus 9 (AAV9) encoding the ABE resulted in substantial, durable correction of the pathogenic mutation (around 20–60% across various organs six months after injection), restoration of normal RNA splicing and reduction of progerin protein levels. In vivo base editing rescued the vascular pathology of the mice, preserving vascular smooth muscle cell counts and preventing adventitial fibrosis. A single injection of ABE-expressing AAV9 at postnatal day 14 improved vitality and greatly extended the median lifespan of the mice from 215 to 510 days. These findings demonstrate the potential of in vivo base editing as a possible treatment for HGPS and other genetic diseases by directly correcting their root cause.

Suggested Citation

  • Luke W. Koblan & Michael R. Erdos & Christopher Wilson & Wayne A. Cabral & Jonathan M. Levy & Zheng-Mei Xiong & Urraca L. Tavarez & Lindsay M. Davison & Yantenew G. Gete & Xiaojing Mao & Gregory A. Ne, 2021. "In vivo base editing rescues Hutchinson–Gilford progeria syndrome in mice," Nature, Nature, vol. 589(7843), pages 608-614, January.
  • Handle: RePEc:nat:nature:v:589:y:2021:i:7843:d:10.1038_s41586-020-03086-7
    DOI: 10.1038/s41586-020-03086-7
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41586-020-03086-7
    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/s41586-020-03086-7?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. Jiajia Lin & Ming Jin & Dong Yang & Zhifang Li & Yu Zhang & Qingquan Xiao & Yin Wang & Yuyang Yu & Xiumei Zhang & Zhurui Shao & Linyu Shi & Shu Zhang & Wan-jin Chen & Ning Wang & Shiwen Wu & Hui Yang , 2024. "Adenine base editing-mediated exon skipping restores dystrophin in humanized Duchenne mouse model," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    3. Hongzhi Zeng & Qichen Yuan & Fei Peng & Dacheng Ma & Ananya Lingineni & Kelly Chee & Peretz Gilberd & Emmanuel C. Osikpa & Zheng Sun & Xue Gao, 2023. "A split and inducible adenine base editor for precise in vivo base editing," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    4. Guiquan Zhang & Yao Liu & Shisheng Huang & Shiyuan Qu & Daolin Cheng & Yuan Yao & Quanjiang Ji & Xiaolong Wang & Xingxu Huang & Jianghuai Liu, 2022. "Enhancement of prime editing via xrRNA motif-joined pegRNA," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    5. 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.
    6. David N. Fiflis & Nicolas A. Rey & Harshitha Venugopal-Lavanya & Beatrice Sewell & Aaron Mitchell-Dick & Katie N. Clements & Sydney Milo & Abigail R. Benkert & Alan Rosales & Sophia Fergione & Aravind, 2024. "Repurposing CRISPR-Cas13 systems for robust mRNA trans-splicing," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    7. Markus Grosch & Laura Schraft & Adrian Chan & Leonie Küchenhoff & Kleopatra Rapti & Anne-Maud Ferreira & Julia Kornienko & Shengdi Li & Michael H. Radke & Chiara Krämer & Sandra Clauder-Münster & Emer, 2023. "Striated muscle-specific base editing enables correction of mutations causing dilated cardiomyopathy," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    8. Daniel Whisenant & Kayeong Lim & Gwladys Revêchon & Haidong Yao & Martin O. Bergo & Piotr Machtel & Jin-Soo Kim & Maria Eriksson, 2022. "Transient expression of an adenine base editor corrects the Hutchinson-Gilford progeria syndrome mutation and improves the skin phenotype in mice," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    9. Qichen Yuan & Xue Gao, 2022. "Multiplex base- and prime-editing with drive-and-process CRISPR arrays," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    10. Chao Yang & Zhenzhen Ma & Keshan Wang & Xingxiao Dong & Meiyu Huang & Yaqiu Li & Xiagu Zhu & Ju Li & Zhihui Cheng & Changhao Bi & Xueli Zhang, 2023. "HMGN1 enhances CRISPR-directed dual-function A-to-G and C-to-G base editing," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    11. Nana Yan & Hu Feng & Yongsen Sun & Ying Xin & Haihang Zhang & Hongjiang Lu & Jitan Zheng & Chenfei He & Zhenrui Zuo & Tanglong Yuan & Nana Li & Long Xie & Wu Wei & Yidi Sun & Erwei Zuo, 2023. "Cytosine base editors induce off-target mutations and adverse phenotypic effects in transgenic mice," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    12. Yanbo Wang & W. Taylor Cottle & Haobo Wang & Momcilo Gavrilov & Roger S. Zou & Minh-Tam Pham & Srinivasan Yegnasubramanian & Scott Bailey & Taekjip Ha, 2022. "Achieving single nucleotide sensitivity in direct hybridization genome imaging," Nature Communications, Nature, vol. 13(1), pages 1-12, 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:589:y:2021:i:7843:d:10.1038_s41586-020-03086-7. 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.