在合理设计的mRNA中增强细胞类型特异性的生成框架
Matvei Khoroshkin1,2,3,4, Arsenii Zinkevich5, Elizaveta Aristova5
1Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
bioRxiv : the preprint server for biology
|January 13, 2025
概括
研究人员开发了PARADE,这是一个AI框架,用于设计具有精确细胞类型特异性的高度稳定的信使RNA (mRNA). 这个平台增强了mRNA疗法,提高了稳定性,疗效,并在临床前模型中减少瘤生长.
科学领域:
- 分子生物学分子生物学
- 生物工程是生物工程.
- 人工智能的人工智能
背景情况:
- 使者RNA (mRNA) 疗法通过使细胞产生治疗性蛋白质,为疾病治疗提供了前景.
- 目前面临的挑战包括高稳定性和可编程细胞类型特定传递的工程mRNA.
- mRNA的未翻译区域 (UTR) 在调节基因表达和稳定性方面发挥着至关重要的作用.
研究的目的:
- 为设计具有增强稳定性和细胞类型特定活性的mRNA未翻译区域 (UTR) 开发一个计算框架.
- 为了改进治疗应用,设计新的mRNA序列.
- 在临床前模型中验证设计的mRNA UTRs的疗效.
主要方法:
- 在六种细胞类型中测量了6万个5'和3'UTR的调节活性.
- 开发了PARADE (mRNA UTRs的预测和理性设计),一个生成AI框架.
- 在细胞系和动物模型中验证了15800个de novo设计的序列.
- 在瘤模型中对瘤抑制器mRNA (PTEN,P16) 进行了PARADE工程UTR测试.
主要成果:
- 与现有的RNA疗法相比,PARADE发现了具有优越细胞类型特异性和活性的新型UTR序列.
- 工程化mRNAs在体内 (肝脏,脏) 显示出强大的组织特异性表达.
- PARADE增强了mRNA稳定性,导致蛋白质产量增加和治疗耐久性.
- 在PARADE设计的UTRs显著降低了神经瘤异种移植和正位素小鼠模型中的瘤生长.
结论:
- PARADE是一个多功能的人工智能平台,用于设计精确,稳定和有效的mRNA疗法.
- 该框架使mRNA UTRs的合理工程能够用于有针对性的治疗应用.
- 这种方法有可能促进下一代基于mRNA的药物的开发.
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