State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China.
Department of Pharmaceutical Analysis, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
Adv Sci (Weinh). 2024 Apr;11(13):e2306792. doi: 10.1002/advs.202306792. Epub 2024 Jan 30.
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.
本研究旨在解决遗传密码扩展中通过定点抑制无义突变来改善非天然氨基酸(UAA)利用率不理想的问题,这对于蛋白质修复和精确性质调整至关重要。通过将 UAA 转化为离子液体,开发出一种简便且经济的口服液体制剂,显著提高了它们的生物利用度和组织积累。实验数据显示,生物利用度提高了 10 倍,焦点组织积累提高了 13 倍,同时 UAA 掺入效率也显著提高。在 Duchenne 肌营养不良症(DMD)模型mdx 小鼠中进行为期 4 周的口服给药,证明了该制剂具有前所未有的治疗潜力,可达 40%的肌营养不良蛋白表达恢复和 75%的正常纤维功能恢复,超过了现有治疗方法,并表现出显著的长期安全性。本研究提供了一种有效的口服剂型,可显著提高 UAA 在体内向靶蛋白的掺入,为无义突变介导的疾病治疗提供了重大进展,具有很大的临床转化潜力。
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