Axonopathy in Duchenne Muscular Dystrophy limits microdystrophin gene therapy efficacy

Abstract

Duchenne muscular dystrophy (DMD) is classically defined as a primary myopathy, and current AAV-mediated microdystrophin gene therapies are shown to successfully preserve muscle integrity. However, their efficacy in recovering functional outcomes remains to improve. We hypothesized that this limitation stems from an unaccounted vulnerability within the peripheral nerve. Here, we demonstrate that the mdx mouse model exhibits a peripheral axonopathy independently of muscle necrosis. Using single-nucleus RNA sequencing and structural analyses, we have identified an active denervation program and a profound failure of neural repair pathways. Importantly, we revealed that the full-length dystrophin isoform Dp427c is expressed in the healthy peripheral nerve, intimately following the cytoskeletal organization and accumulating at regions of high biomechanical stress, including SchmidtLanterman incisures and Nodes of Ranvier. In its absence, nerves of mdx mice loss an essential scaffolding support, leading to localized structural collapse. Furthermore, we showed that muscle-restricted microdystrophin gene therapy rescues sarcolemmal integrity but failed to restore nerve-muscle connectivity or resolved neurotransmission defects. These findings fundamentally redefine DMD as an integrated motor unit pathology, thereby underscoring the absolute necessity of implementing combined therapeutic strategies that target both the muscle and the peripheral nervous system.

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BibTeX RIS

BibTeX

@misc{bourguibavilleneuve2026axonopathy,
  title = {{Axonopathy in Duchenne Muscular Dystrophy limits microdystrophin gene therapy efficacy}},
  author = {Aly Bourguiba-Villeneuve and Maxime Gelin and Aurélie Fail and Lucile Saillard and Stéphanie Bauché and Cécile Peccate and Pierre Meunier and Zoheir Guesmia and Lou Ann Mirabile and Julianne Perronnet and Mégane Lemaitre and Lorenzo Giordani and Sestina Falcone and Christel Gentil and France Piétri‐rouxel},
  howpublished = {HAL},
  year = {2026},
  month = aug,
  doi = {10.64898/2026.08.17.744857},
  url = {https://hal.science/hal-05769832v1},
  note = {CC BY-NC-ND 4.0},
}

RIS

TY  - UNPB
TI  - Axonopathy in Duchenne Muscular Dystrophy limits microdystrophin gene therapy efficacy
AU  - Aly Bourguiba-Villeneuve
AU  - Maxime Gelin
AU  - Aurélie Fail
AU  - Lucile Saillard
AU  - Stéphanie Bauché
AU  - Cécile Peccate
AU  - Pierre Meunier
AU  - Zoheir Guesmia
AU  - Lou Ann Mirabile
AU  - Julianne Perronnet
AU  - Mégane Lemaitre
AU  - Lorenzo Giordani
AU  - Sestina Falcone
AU  - Christel Gentil
AU  - France Piétri‐rouxel
PY  - 2026
DA  - 2026/08/20
PB  - HAL
DO  - 10.64898/2026.08.17.744857
UR  - https://hal.science/hal-05769832v1
AB  - Duchenne muscular dystrophy (DMD) is classically defined as a primary myopathy, and current AAV-mediated microdystrophin gene therapies are shown to successfully preserve muscle integrity. However, their efficacy in recovering functional outcomes remains to improve. We hypothesized that this limitation stems from an unaccounted vulnerability within the peripheral nerve. Here, we demonstrate that the mdx mouse model exhibits a peripheral axonopathy independently of muscle necrosis. Using single-nucleus RNA sequencing and structural analyses, we have identified an active denervation program and a profound failure of neural repair pathways. Importantly, we revealed that the full-length dystrophin isoform Dp427c is expressed in the healthy peripheral nerve, intimately following the cytoskeletal organization and accumulating at regions of high biomechanical stress, including SchmidtLanterman incisures and Nodes of Ranvier. In its absence, nerves of mdx mice loss an essential scaffolding support, leading to localized structural collapse. Furthermore, we showed that muscle-restricted microdystrophin gene therapy rescues sarcolemmal integrity but failed to restore nerve-muscle connectivity or resolved neurotransmission defects. These findings fundamentally redefine DMD as an integrated motor unit pathology, thereby underscoring the absolute necessity of implementing combined therapeutic strategies that target both the muscle and the peripheral nervous system.
ER  -

Abstract

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