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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
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    References listed on IDEAS

    as
    1. 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.
    2. 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.
    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. 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.
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