Activation of endogenous full-length utrophin by MyoAAV-UA as a therapeutic approach for Duchenne muscular dystrophy
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| Publicado en: | Nature Communications vol. 16, no. 1 (2025), p. 2398 |
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| Publicado: |
Nature Publishing Group
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| Materias: | |
| Acceso en línea: | Citation/Abstract Full Text - PDF |
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| Resumen: | Activation of endogenous full-length utrophin, a dystrophin homolog, presents an attractive therapeutic strategy for Duchenne muscular dystrophy (DMD), regardless of mutation types and loci. However, current dCas9-based activators are too large for efficient adeno-associated virus delivery, and the feasibility and durability of such treatments remain unclear. Here, we develop a muscle-targeted utrophin activation system using the compact dCasMINI-VPR system, termed MyoAAV-UA. Systemic administration of MyoAAV-UA in male mdx mice leads to substantial upregulation of utrophin at the sarcolemma, resulting in significant improvements in skeletal muscle function and a slowing of heart function deterioration. These benefits remain observable at six months post-treatment. In male nonhuman primates, systemic administration of MyoAAV-UA increases utrophin expression by twofold in skeletal muscle, with no significant side effects observed. Furthermore, MyoAAV-UA upregulates utrophin and utrophin-glycoprotein complexes in induced pluripotent stem cell-derived myotubes from DMD patients. In conclusion, these findings demonstrate the potential of MyoAAV-UA as a therapeutic approach for DMD.Duchenne muscular dystrophy (DMD) is a fatal genetic disorder caused by mutations in the DMD gene. Here, the authors develop MyoAAV-UA, a compact utrophin activator, as a promising universal treatment for DMD through a homologous protein activation approach. |
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| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-025-57831-5 |
| Fuente: | Health & Medical Collection |