Algorithm for optimized mRNA design improves stability and immunogenicity

【Abstract】

Messenger RNA (mRNA) vaccines are being used to combat the spread of COVID-19(refs. 1–3), but they still exhibit critical limitations caused by mRNA instability and degradation, which are major obstacles for the storage, distribution and efficacy of the vaccine products4. Increasing secondary structure lengthens mRNA half-life, which, together with optimal codons, improves protein expression5. Therefore, a principled mRNA design algorithm must optimize both structural stability and codon usage. However, owing to synonymous codons, the mRNA design space is prohibitively large—for example, there are around 2.4 × 10632 candidate mRNA sequences for the SARS-CoV-2 spike protein. This poses insurmountable computational challenges. Here we provide a simple and unexpected solution using the classical concept of lattice parsing in computational linguistics, where finding the optimal mRNA sequence is analogous to identifying the most likely sentence among similar-sounding alternatives6. Our algorithm LinearDesign finds an optimal mRNA design for the spike protein in just 11 minutes, and can concurrently optimize stability and codon usage. LinearDesign substantially improves mRNA half-life and protein expression, and profoundly increases antibody titre by up to 128 times in mice compared to the codon-optimization benchmark on mRNA vaccines for COVID-19 and varicella-zoster virus. This result reveals the great potential of principled mRNA design and enables the exploration of previously unreachable but highly stable and efficient designs.
Our work is a timely tool for vaccines and other mRNA-based medicines encoding therapeutic proteins such as monoclonal antibodies and anti-cancer drugs7,8.

相信大家肯定都聽過全球最權威的三大學術期刊《Nature》、《Science》和《Cell》，其中影響係數(IF)最高的《Nature》在各領域更具有舉足輕重的地位，雖然光鼎Qsep系列產品不是第一次被這三大期刊提及(Nature 38篇/ Science 6篇/ Cell 12篇)，但本次可是搭配了mRNA的新應用而首度登上Nature主刊的版面!!!

辛苦多年的研究成果要在《Nature》上發表有多難?每年來自全球約13萬件送審的文章中，約有11萬件在第一階段會被否決，剩餘件數僅剩21%會被送審，送審後也僅有32%會通過審核，結算僅約1%的文章會被納入，一般若能成功在此發布文章，便等同受到國際認可，對科研、學校單位乃至作者本身更是一件如鑲了金般的大喜事。

在新冠疫情爆發後，mRNA技術被更廣泛的利用在疫苗及藥物開發，而mRNA分子本身容易降解且穩定性較差，為了克服這樣的處境，本次羅徹斯特大學、奧勒岡州立大學、斯微生物科技、百度美國研究院等單位，合作利用AI來優化mRNA的序列設計，並成功在《Nature》第621期主刊中發表，強調能夠更快速的設計出穩定的mRNA序列，經比對，不論是在穩定性、蛋白質表現量皆優於傳統方法。

光鼎Qsep系列產品所扮演的角色，即是整個實驗流程最核心的一環: 驗證mRNA的完整性，若mRNA的完整性不足，在後面的程序也將無法如預期發揮功效。WHO和FDA已將毛細管電泳的驗證編訂在現今mRNA製劑的品檢中。而Qsep系列產品因具有操作簡便、高解析、高靈敏、高再現性等多重特性，獲得全球六十幾國生醫相關單位採用，相信未來在mRNA疫苗及藥物的毛細管電泳新應用方向，Qsep將可成為研發及應用上最佳工具。

讓我們一起站上巨人的肩膀吧! Nature期刊連結:

https://www.nature.com/articles/s41586-023-06127-z

我們的產品都上Nature了，你還不來看看嗎?

https://www.youtube.com/channel/UCxfN9NTZchfXS2ahZI0NA3Q 

想開啟您與Nature的連結嗎?快聯絡我們的專業團隊!

sales@bioptic.com.tw
https://www.bioptic.com.tw

#BiOptic #Qsep #Nature #mRNA