Unnatural Amino Acid-Based Ionic Liquid Enables Oral Treatment of Nonsense Mutation Disease in Mice
© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH..
This investigation addresses the challenge of suboptimal unnatural amino acid (UAA) utilization in the site-specific suppression of nonsense mutations through genetic code expansion, which is crucial for protein restoration and precise property tailoring. A facile and economical oral liquid formulation is developed by converting UAAs into ionic liquids, significantly enhancing their bioavailability and tissue accumulation. Empirical data reveal a 10-fold increase in bioavailability and up to a 13-fold rise in focal tissue accumulation, alongside marked improvements in UAA incorporation efficiency. A 4-week oral administration in mdx mice, a model for Duchenne muscular dystrophy (DMD), demonstrates the formulation's unprecedented therapeutic potential, with up to 40% dystrophin expression restoration and 75% recovery of normal fiber functions, surpassing existing treatments and exhibiting substantial long-term safety. This study presents a potent oral dosage form that dramatically improves UAA incorporation into target proteins in vivo, offering a significant advance in the treatment of nonsense mutation-mediated disorders and holding considerable promise for clinical translation.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
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| Enthalten in: |
Advanced science (Weinheim, Baden-Wurttemberg, Germany) - 11(2024), 13 vom: 03. Apr., Seite e2306792 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Shi, Yujie [VerfasserIn] |
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| Links: |
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| Themen: |
Amino Acids |
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| Anmerkungen: |
Date Completed 04.04.2024 Date Revised 04.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/advs.202306792 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a This investigation addresses the challenge of suboptimal unnatural amino acid (UAA) utilization in the site-specific suppression of nonsense mutations through genetic code expansion, which is crucial for protein restoration and precise property tailoring. A facile and economical oral liquid formulation is developed by converting UAAs into ionic liquids, significantly enhancing their bioavailability and tissue accumulation. Empirical data reveal a 10-fold increase in bioavailability and up to a 13-fold rise in focal tissue accumulation, alongside marked improvements in UAA incorporation efficiency. A 4-week oral administration in mdx mice, a model for Duchenne muscular dystrophy (DMD), demonstrates the formulation's unprecedented therapeutic potential, with up to 40% dystrophin expression restoration and 75% recovery of normal fiber functions, surpassing existing treatments and exhibiting substantial long-term safety. This study presents a potent oral dosage form that dramatically improves UAA incorporation into target proteins in vivo, offering a significant advance in the treatment of nonsense mutation-mediated disorders and holding considerable promise for clinical translation | ||
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| 700 | 1 | |a Xia, Qing |e verfasserin |4 aut | |
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