IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-50340-x.html
   My bibliography  Save this article

Adenine base editing-mediated exon skipping restores dystrophin in humanized Duchenne mouse model

Author

Listed:
  • Jiajia Lin

    (Fujian Medical University)

  • Ming Jin

    (Fujian Medical University)

  • Dong Yang

    (HuidaGene Therapeutics Inc.)

  • Zhifang Li

    (Lingang Laboratory)

  • Yu Zhang

    (HuidaGene Therapeutics Inc.)

  • Qingquan Xiao

    (HuidaGene Therapeutics Inc.)

  • Yin Wang

    (HuidaGene Therapeutics Inc.)

  • Yuyang Yu

    (HuidaGene Therapeutics Inc.)

  • Xiumei Zhang

    (HuidaGene Therapeutics Inc.)

  • Zhurui Shao

    (HuidaGene Therapeutics Inc.)

  • Linyu Shi

    (HuidaGene Therapeutics Inc.)

  • Shu Zhang

    (First Medical Center of Chinese PLA General Hospital)

  • Wan-jin Chen

    (Fujian Medical University)

  • Ning Wang

    (Fujian Medical University)

  • Shiwen Wu

    (First Medical Center of Chinese PLA General Hospital)

  • Hui Yang

    (HuidaGene Therapeutics Inc.
    Shanghai Center for Brain Science and Brain-Inspired Technology)

  • Chunlong Xu

    (Lingang Laboratory
    Shanghai Center for Brain Science and Brain-Inspired Technology)

  • Guoling Li

    (Fujian Medical University
    HuidaGene Therapeutics Inc.)

Abstract

Duchenne muscular dystrophy (DMD) affecting 1 in 3500–5000 live male newborns is the frequently fatal genetic disease resulted from various mutations in DMD gene encoding dystrophin protein. About 70% of DMD-causing mutations are exon deletion leading to frameshift of open reading frame and dystrophin deficiency. To facilitate translating human DMD-targeting CRISPR therapeutics into patients, we herein establish a genetically humanized mouse model of DMD by replacing exon 50 and 51 of mouse Dmd gene with human exon 50 sequence. This humanized mouse model recapitulats patient’s DMD phenotypes of dystrophin deficiency and muscle dysfunction. Furthermore, we target splicing sites in human exon 50 with adenine base editor to induce exon skipping and robustly restored dystrophin expression in heart, tibialis anterior and diaphragm muscles. Importantly, systemic delivery of base editor via adeno-associated virus in the humanized male mouse model improves the muscle function of DMD mice to the similar level of wildtype ones, indicating the therapeutic efficacy of base editing strategy in treating most of DMD types with exon deletion or point mutations via exon-skipping induction.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50340-x
    DOI: 10.1038/s41467-024-50340-x
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-50340-x
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-50340-x?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
    ---><---

    References listed on IDEAS

    as
    1. Leonela Amoasii & Hui Li & Yu Zhang & Yi-Li Min & Efrain Sanchez-Ortiz & John M. Shelton & Chengzu Long & Alex A. Mireault & Samadrita Bhattacharyya & John R. McAnally & Rhonda Bassel-Duby & Eric N. O, 2019. "In vivo non-invasive monitoring of dystrophin correction in a new Duchenne muscular dystrophy reporter mouse," Nature Communications, Nature, vol. 10(1), pages 1-8, December.
    2. 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.
    3. Li Xu & Chen Zhang & Haiwen Li & Peipei Wang & Yandi Gao & Nahush A. Mokadam & Jianjie Ma & W. David Arnold & Renzhi Han, 2021. "Efficient precise in vivo base editing in adult dystrophic mice," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    4. Janice S. Chen & Yavuz S. Dagdas & Benjamin P. Kleinstiver & Moira M. Welch & Alexander A. Sousa & Lucas B. Harrington & Samuel H. Sternberg & J. Keith Joung & Ahmet Yildiz & Jennifer A. Doudna, 2017. "Enhanced proofreading governs CRISPR–Cas9 targeting accuracy," Nature, Nature, vol. 550(7676), pages 407-410, October.
    5. Nicole M. Gaudelli & Alexis C. Komor & Holly A. Rees & Michael S. Packer & Ahmed H. Badran & David I. Bryson & David R. Liu, 2017. "Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage," Nature, Nature, vol. 551(7681), pages 464-471, November.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. 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.
    2. Lin Zhao & Sabrina R. T. Koseki & Rachel A. Silverstein & Nadia Amrani & Christina Peng & Christian Kramme & Natasha Savic & Martin Pacesa & Tomás C. Rodríguez & Teodora Stan & Emma Tysinger & Lauren , 2023. "PAM-flexible genome editing with an engineered chimeric Cas9," Nature Communications, Nature, vol. 14(1), pages 1-8, December.
    3. Daphne Collias & Elena Vialetto & Jiaqi Yu & Khoa Co & Éva d. H. Almási & Ann-Sophie Rüttiger & Tatjana Achmedov & Till Strowig & Chase L. Beisel, 2023. "Systematically attenuating DNA targeting enables CRISPR-driven editing in bacteria," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    4. 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.
    5. 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.
    6. Chengdong Zhang & Yuan Yang & Tao Qi & Yuening Zhang & Linghui Hou & Jingjing Wei & Jingcheng Yang & Leming Shi & Sang-Ging Ong & Hongyan Wang & Hui Wang & Bo Yu & Yongming Wang, 2023. "Prediction of base editor off-targets by deep learning," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    7. Yuan Zhou & Chen Zhang & Weidong Xiao & Roland W. Herzog & Renzhi Han, 2024. "Systemic delivery of full-length dystrophin in Duchenne muscular dystrophy mice," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    8. 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.
    9. 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.
    10. 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.
    11. Péter István Kulcsár & András Tálas & Zoltán Ligeti & Sarah Laura Krausz & Ervin Welker, 2022. "SuperFi-Cas9 exhibits remarkable fidelity but severely reduced activity yet works effectively with ABE8e," Nature Communications, Nature, vol. 13(1), pages 1-11, 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.
    13. Burcu Bestas & Sandra Wimberger & Dmitrii Degtev & Alexandra Madsen & Antje K. Rottner & Fredrik Karlsson & Sergey Naumenko & Megan Callahan & Julia Liz Touza & Margherita Francescatto & Carl Ivar Möl, 2023. "A Type II-B Cas9 nuclease with minimized off-targets and reduced chromosomal translocations in vivo," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    14. 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.
    15. 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.
    16. Péter István Kulcsár & András Tálas & Zoltán Ligeti & Eszter Tóth & Zsófia Rakvács & Zsuzsa Bartos & Sarah Laura Krausz & Ágnes Welker & Vanessza Laura Végi & Krisztina Huszár & Ervin Welker, 2023. "A cleavage rule for selection of increased-fidelity SpCas9 variants with high efficiency and no detectable off-targets," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    17. Haiwen Li & Peipei Wang & Chen Zhang & Yuanbojiao Zuo & Yuan Zhou & Renzhi Han, 2023. "Defective BVES-mediated feedback control of cAMP in muscular dystrophy," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    18. Kayeong Lim & Sung-Ik Cho & Jin-Soo Kim, 2022. "Nuclear and mitochondrial DNA editing in human cells with zinc finger deaminases," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    19. Giulia I. Corsi & Kunli Qu & Ferhat Alkan & Xiaoguang Pan & Yonglun Luo & Jan Gorodkin, 2022. "CRISPR/Cas9 gRNA activity depends on free energy changes and on the target PAM context," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    20. Zeyu Lu & Lingtian Zhang & Qing Mu & Junyang Liu & Yu Chen & Haoyuan Wang & Yanjun Zhang & Rui Su & Ruijun Wang & Zhiying Wang & Qi Lv & Zhihong Liu & Jiasen Liu & Yunhua Li & Yanhong Zhao, 2024. "Progress in Research and Prospects for Application of Precision Gene-Editing Technology Based on CRISPR–Cas9 in the Genetic Improvement of Sheep and Goats," Agriculture, MDPI, vol. 14(3), pages 1-17, March.

    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:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50340-x. 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.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with 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.