I-Corps: Identification of a stable hybrid carrier for large-scale expression of recombinant miRNAs and siRNAs in E. coli

I-Corps项目更广泛的影响/商业潜力侧重于开发高产量、高成本效益的天然RNA干扰（RNAi）药物生产平台。该项目解决了在治疗和转化研究中开发天然rna为基础的药物的日益增长的兴趣。由于基于rna的药物具有接近其他方法无法达到的靶标（如小分子和蛋白质）的能力，该项目将为用自然产生的药物治疗不治之症开辟新的方向。通过利用发酵技术，本研究可能为学术研究机构和制药公司带来高成本效益的天然rna药物生产。如果成功，该项目将建立一个新的RNAi生物工程平台。这个I-Corps项目是基于鉴定一个稳定的、完全人源化的杂交载体，用于在大肠杆菌的常见菌株中大规模表达重组微RNA （miRNA）和小干扰RNA （siRNA）。当前的RNA干扰（RNAi）研究和开发通常局限于使用化学工程或合成的RNAi试剂，这些试剂需要进行各种广泛的人工修饰以保持稳定性。这些人工修饰可引起免疫原性。该项目的总体目的是开发一个独特的平台，用于经济和可持续地生产在活细胞中生产和折叠的天然RNAi试剂。早期的研究表明，生物工程miRNA/siRNA制剂携带很少的天然转录后修饰核苷，并在人类细胞和小鼠模型中表现出良好的稳定性。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact/commercial potential of this I-Corps project focuses on the development of a high-yield, cost-effective production platform for natural RNA interference (RNAi) agents. This project addresses the increasing interest in developing natural RNA-based agents for therapeutics and translational research. Since RNA-based drugs have the capability to approach targets (such as small molecules and proteins) that are unavailable by other methods, this project will open new directions for treating incurable diseases with naturally produced drugs. With the use of fermentation technology, this research may result in the cost-effective production of natural RNA-based drugs for both academic research institutes and pharmaceutical companies. If successful, this project will establish a novel RNAi bioengineering platform.This I-Corps project is based on the identification of a stable, fully humanized hybrid carrier for large-scale expression of recombinant micro RNA (miRNA) and small interfering RNA (siRNA) in a common strain of E. coli. Current RNA interference (RNAi) research and development is often limited to the use of chemically-engineered or synthesized RNAi agents that require various and extensive artificial modifications for stability. These artificial modifications can provoke immunogenicity. The overall purpose of this project is the development of a unique platform for the economical and sustainable production of natural RNAi agents that are produced and folded in living cells. Early work has demonstrated that bioengineered miRNA/siRNA agents carry few natural post transcriptionally-modified nucleosides and exhibit favorable stability within human cells and mouse models.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.