IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-50569-6.html
   My bibliography  Save this article

Systemic delivery of full-length dystrophin in Duchenne muscular dystrophy mice

Author

Listed:
  • Yuan Zhou

    (Indiana University School of Medicine
    Central South University)

  • Chen Zhang

    (Indiana University School of Medicine)

  • Weidong Xiao

    (Indiana University School of Medicine)

  • Roland W. Herzog

    (Indiana University School of Medicine)

  • Renzhi Han

    (Indiana University School of Medicine)

Abstract

Current gene therapy for Duchenne muscular dystrophy (DMD) utilizes adeno-associated virus (AAV) to deliver micro-dystrophin (µDys), which does not provide full protection for striated muscles as it lacks many important functional domains of full-length (FL) dystrophin. Here we develop a triple vector system to deliver FL-dystrophin into skeletal and cardiac muscles. We split FL-dystrophin into three fragments linked to two orthogonal pairs of split intein, allowing efficient assembly of FL-dystrophin. The three fragments packaged in myotropic AAV (MyoAAV4A) restore FL-dystrophin expression in both skeletal and cardiac muscles in male mdx4cv mice. Dystrophin-glycoprotein complex components are also restored at the sarcolemma of dystrophic muscles. MyoAAV4A-delivered FL-dystrophin significantly improves muscle histopathology, contractility, and overall strength comparable to µDys, but unlike µDys, it also restores defective cavin 4 localization and associated signaling in mdx4cv heart. Therefore, our data support the feasibility of a mutation-independent FL-dystrophin gene therapy for DMD, warranting further clinical development.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50569-6
    DOI: 10.1038/s41467-024-50569-6
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-50569-6
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-50569-6?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. Jonas Weinmann & Sabrina Weis & Josefine Sippel & Warut Tulalamba & Anca Remes & Jihad El Andari & Anne-Kathrin Herrmann & Quang H. Pham & Christopher Borowski & Susanne Hille & Tanja Schönberger & No, 2020. "Identification of a myotropic AAV by massively parallel in vivo evaluation of barcoded capsid variants," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    2. 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.
    3. John T. Olthoff & Angus Lindsay & Reem Abo-Zahrah & Kristen A. Baltgalvis & Xiaobai Patrinostro & Joseph J. Belanto & Dae-Yeul Yu & Benjamin J. Perrin & Daniel J. Garry & George G. Rodney & Dawn A. Lo, 2018. "Loss of peroxiredoxin-2 exacerbates eccentric contraction-induced force loss in dystrophin-deficient muscle," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    4. 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.
    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. 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.
    2. Fatma-Elzahraa Eid & Albert T. Chen & Ken Y. Chan & Qin Huang & Qingxia Zheng & Isabelle G. Tobey & Simon Pacouret & Pamela P. Brauer & Casey Keyes & Megan Powell & Jencilin Johnston & Binhui Zhao & K, 2024. "Systematic multi-trait AAV capsid engineering for efficient gene delivery," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. 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.
    4. 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.
    5. Marco Thürkauf & Shuo Lin & Filippo Oliveri & Dirk Grimm & Randall J. Platt & Markus A. Rüegg, 2023. "Fast, multiplexable and efficient somatic gene deletions in adult mouse skeletal muscle fibers using AAV-CRISPR/Cas9," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    6. Trevor J. Gonzalez & Katherine E. Simon & Leo O. Blondel & Marco M. Fanous & Angela L. Roger & Maribel Santiago Maysonet & Garth W. Devlin & Timothy J. Smith & Daniel K. Oh & L. Patrick Havlik & Ruth , 2022. "Cross-species evolution of a highly potent AAV variant for therapeutic gene transfer and genome editing," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    7. Ai Vu Hong & Laurence Suel & Eva Petat & Auriane Dubois & Pierre-Romain Le Brun & Nicolas Guerchet & Philippe Veron & Jérôme Poupiot & Isabelle Richard, 2024. "An engineered AAV targeting integrin alpha V beta 6 presents improved myotropism across species," Nature Communications, Nature, vol. 15(1), pages 1-20, 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:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50569-6. 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.