Unnatural Amino Acid-Based Ionic Liquid Enables Oral Treatment of Nonsense Mutation Disease in Mice.
Adv Sci (Weinh)
; 11(13): e2306792, 2024 Apr.
Article
em En
| MEDLINE
| ID: mdl-38288517
ABSTRACT
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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Base de dados:
MEDLINE
Assunto principal:
Distrofia Muscular de Duchenne
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Líquidos Iônicos
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article