2020, the First Era of mRNA Therapy

COVID-19 ravaged the world and caused huge losses to human society, but it has accelerated the research and development of mRNA drugs. Some people call 2020 "the first year of mRNA technology." Progress in mRNA drug development In 1990, Wolff et al. demonstrated for the first time that direct injection of mRNA into mice can produce active protein that has a dose substitution. This direct injection of mRNA and expression of specific proteins to produce therapeutic effects is the embryonic form of mRNA therapy. Katalin Karikó from the University of Pennsylvania proposed that mRNA therapy (https://mrna.creative-biolabs.com/) could be an alternative to DNA therapy. mRNA is not a molecule that is easy to manipulate, which is not as stable as DNA and protein and is easily degraded. More importantly, even if mRNA can be stably extracted and injected into animals, it will cause a series of immune responses. Therefore, it has huge hidden dangers. This problem was solved in 2005. Professor Karikó and Professor Drew Weissmam found that the key to the immune response caused by mRNA is uracil. After simple modification of the nucleoside of uracil, "pseudouracil" is produced, which can avoid the monitoring of the immune system, thereby solving the problem of immune response, and thus, the curtain of mRNA therapy unveiled. Advantages of mRNA drugs: * Play a role in mitotic and non-mitotic cells without entering the nucleus. * Predictable duration of the mRNA-encoded protein (days or weeks). * Unlike pDNA and viral vectors, mRNA does not contain other foreign genes, so it is purer and safer as a vector. * mRNA can be synthesized in vitro through cell-free technology, which greatly reduces the possibility of contamination by other components and meets GMP production requirements. The multiple advantages and prospects of mRNA drugs attracted many biotechnology companies to join the R&D of related drugs. Prevention of infectious disease (mRNA vaccine) mRNA vaccine refers to the delivery of mRNA encoding antigen protein into human cells through different technical means, expressing and translating into the required antigen protein, and stimulating the body to produce a specific immune response. Compared with traditional vaccine, mRNA vaccine is designed based on the conserved regions of the virus, which directly translates into specific antigens in cells to activate the body's immune response to produce antibodies. At present, global innovative pharmaceutical companies are making every effort to develop drugs and vaccines against the COVID-19. Among them, the most noteworthy are the mRNA vaccine candidates. Other mRNA vaccines for the prevention of other infectious diseases mainly targets influenza virus, respiratory syncytial virus (RSV), and HIV. mRNA vaccine pipelines in the mid-to-late stage Drug Company Status Disease Targetrntozinameran BioNTech/Pfizer/Fosunpharma FDA approved COVID-19 SARS-CoV-2 SrnmRNA-1273 Moderna FDA approved COVID-19 SARS-CoV-2 SrnBNT-162b3 BioNTech/Pfizer Phase II COVID-19 -rnmRNA-1647 Moderna Phase II Cytomegalovirus infection Human cytomegalovirus EGP B and HrnSARS-CoV-2 mRNA vaccine CureVac Pre-registration COVID-19 SARS-CoV-2 SrnARCT-021 Arcturus/Duke-NUS Phase II COVID-19 - From the perspective of commercial production, although the target antigens vary, the preparation and purification processes of most mRNA vaccines are basically similar. The target mRNA sequence can be obtained quickly with standardized templates, which can greatly save time and costs of R&D and production. Compared with the traditional vaccine production cycle of 6-8 months, mRNA vaccines are expected to complete sample preparation within 40 days, and GMP production and QC can be completed within 3 months. It has natural advantages in dealing with large-scale epidemics such as the COVID-19. Tumor treatment Depending on the route of administration, therapeutic mRNA tumor vaccines can be divided into two categories, which are mRNA vaccines based on dendritic cell (DC) administration and direct injection of mRNA vaccines. At present, companies researching mRNA tumor vaccine mainly include Moderna, BioNTech, and CureVac. Rare disease treatment mRNA drugs can also be used for the treatment of rare diseases. Translate Bio's MRT-5005 (target: CFTR gene) for the treatment of cystic fibrosis has entered the phase 2 clinic study. For years, mRNA drugs have shown great potentials in the prevention and treatment of infectious diseases, cancer, and rare disease. Innovative pharmaceutical companies around the world have rushed to invest in the R&D in related fields. Based on continuous deep cultivation and accumulation in the field of biotechnology, CRO companies represented by Creative Biolabs are actively building a technology platform for mRNA drug R&D and production to assist with the industry's innovation and development.