Development of superior polymerases for next-generation mRNA therapeutic & vaccine manufacturing

开发用于下一代 mRNA 治疗的优质聚合酶

• 批准号: 10229603
• 负责人: Helge Zieler
• 金额: $ 46.93万
• 依托单位: PRIMORDIAL GENETICS, INC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-17 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10229603
• 关键词: Agricultural Crops; Agriculture; Animals; Attention; Biotechnology; Carrier Proteins; Cells; Chemical Structure; Clinical; Code; Communicable Diseases; Cystic Fibrosis; DNA-Directed RNA Polymerase; Data Set; Development; Disease; Double-Stranded RNA; Drug Industry; Enzymes; Gene Expression; Genetic; Genetic Carriers; Genetic Diseases; Goals; HIV; Health; Hepatitis; Hepatitis B; Heritability; Human; Human body; In Vitro; Industry; Investments; Length; Malignant Neoplasms; Medicine; Methods; Mutation; Nucleotides; Organism; Performance; Pharmacologic Substance; Phase; Play; Polymerase; Prevention; Production; Promoter Regions; Property; RNA; RNA chemical synthesis; Rare Diseases; Reaction; Reagent; Regulator Genes; Running; Sales; Side; Small Business Innovation Research Grant; Structure; System; Testing; Therapeutic; Time; TimeLine; Vaccines; Variant; Virus Diseases; Work; base; cancer therapy; clinical efficacy; commercialization; flexibility; genetic information; improved; in vitro testing; interest; meetings; next generation; novel; novel therapeutics; novel vaccines; promoter; research and development; scale up; therapeutic RNA

Project Summary/Abstract Messenger ribonucleic acid (mRNA) plays key roles in cells and organisms as a carrier of protein-coding information and as a regulator of gene expression. The pharmaceutical industry has begun to exploit the many natural functions of mRNA to develop novel therapeutics and vaccines, which promise high efficacy and great flexibility in the prevention and treatment of diseases ranging from cancers and infectious diseases such as hepatitis and HIV to genetic diseases such as cystic fibrosis and rare diseases caused by heritable genetic defects. The expanded effort in mRNA therapeutics and mRNA vaccines has created a new demand for mRNA molecules manufactured in large quantities to precise specifications. In particular, the need to create mRNA molecules >1kb in length that are free of unwanted side products, and to incorporate modified nucleotides for more efficient delivery, higher stability and better clinical efficacy, has compounded this manufacturing problem. Although RNAs can be produced enzymatically in vitro with the use of specialized RNA polymerases, the enzymes widely used to produce RNA for R&D purposes are not suited for the demanding specifications that apply to RNA molecules intended for mRNA therapeutics and vaccines. A new class of enzymes, highly optimized for synthesis of long RNAs with specific sequences and structures, need to be created to meet this new demand. In a Phase I feasibility project, Primordial Genetics discovered and tested 53 novel RNA polymerases of which 13 were found to be superior to the current enzymes used for RNA manufacturing. On the strength of our Phase I results, the company began to forge connections to RNA therapeutics companies who are very interested in testing our new enzymes. In the proposed Phase II project, we will improve four of these enzymes, characterize the activity of six improved enzymes in detail, and prepare methods and datasets for using these enzymes for clinical mRNA manufacturing. Our goal is to create enzymes that can meet the varied needs for manufacturing a diversity of mRNA sequences, sizes and chemical structures represented in mRNA vaccines and mRNA therapeutic products under development. The enzymes discovered and improved in this work will be directly useful for mRNA manufacturing applications, and will be licensed or sold to companies developing mRNA vaccines and therapeutics as well as companies building RNA manufacturing capabilities.

项目摘要/摘要 信使核糖核酸（mRNA）在细胞和生物中起关键作用，作为载体 蛋白质编码信息和作为​​基因表达的调节剂。制药行业有 开始利用mRNA的许多自然功能来开发新型的治疗剂和疫苗， 哪些有望在预防和治疗疾病方面具有很高的效力和极大的灵活性 从癌和感染性疾病（如肝炎和艾滋病毒）到遗传疾病的范围 作为遗传缺陷引起的囊性纤维化和罕见疾病。 mRNA疗法和mRNA疫苗方面的扩大努力为 大量生产的mRNA分子符合精确的规格。特别是需要 创建不含不必要的侧产品的长度> 1kb的mRNA分子，然后 结合改良的核苷酸，以提高效率，更高的稳定性和更好的临床 功效，使这个制造问题更加复杂。虽然可以生产RNA 通过使用专门的RNA聚合酶在体外酶促，该酶广泛用于 用于研发目的的RNA不适合适用于RNA的苛刻规格 用于mRNA疗法和疫苗的分子。一类新的酶，高度 优化用于与特定序列和结构的长RNA合成，需要创建 满足这个新需求。 在I阶段的可行性项目中，原始遗传学发现并测试了53个新型RNA 发现13个聚合酶优于用于RNA的当前酶 制造业。在我们阶段的结果上，公司开始建立联系 对测试我们的新酶非常感兴趣的RNA治疗公司。 在拟议的II期项目中，我们将改善这些酶的四种，以表征 详细的六个改进酶的活动，并准备使用这些酶的方法和数据集 用于临床mRNA制造的酶。我们的目标是创建可以符合多样化的酶 制造多样性的mRNA序列，大小和化学结构的需求 在开发的mRNA疫苗和mRNA治疗产物中代表。酶 在这项工作中发现和改进将直接用于mRNA制造应用， 并将获得许可或出售给开发mRNA疫苗和治疗剂的公司以及 建立RNA制造能力的公司。