RNA Therapy—Center of Next-generation Innovative Therapies: Chapter I

RNA drugs directly interfere with the process of gene transcription and translation, the essence of which is gene therapy. Traditional gene therapy in a narrow sense generally refers to directly modifying the disease-causing genes of target cells or introducing foreign copies of normal genes. However, RNA therapy focuses more on the regulation of gene expression, which is a generalized gene therapy. There are more than 100 modifications that have been found on RNA, providing it with additional regulatory information in addition to base sequence information. The result is that at the same transcription level, the total amount of protein produced and the time distribution vary, and the same gene sequence can also be translated into different protein sequences due to different RNA splicing. Therefore, theoretically, interventions at the RNA level are far more abundant than at the DNA level. Classification of RNA therapiesrnAfter years of development, the gene therapy industry has developed toward different directions. According to the persistence of gene expression regulation, it can be divided into two categories. One is permanent gene modification, including in vivo gene editing technology represented by CRISPR and in vitro gene modification represented by CAR-T technology. The other is RNA-based non-permanent gene therapy. Compared with permanent gene modification, RNA therapy does not require nuclear introduction and nuclear transcription, and there is no need to worry about the risk of cancer or other normal gene inactivation due to non-targeted gene modification. RNA therapy can be further divided into several tracks. Current drug R&D hotspots focus on messenger RNA (mRNA: https://mrna.creative-biolabs.com/), RNA interference (RNAi), and antisense oligonucleotides (ASO) therapy. * The principle of mRNA therapy (https://mrna.creative-biolabs.com/applications-of-mrna-as-therapeutics.htm) is to introduce exogenous mRNA into target cells so that the target cells can synthesize the target protein by themselves. * RNAi therapy utilizes a mechanism that is ubiquitous in the biological world to resist the invasion of foreign genes. At present, the most mature is the use of short interfering RNAs (siRNA) to form RNA-induced silencing complex (RISC), which ultimately degrades the mRNA of the target gene. * Antisense therapy uses single-stranded RNA or DNA to pair with target RNA (mRNA, miRNA, pre-mRNA, etc.) to induce degradation (double-stranded RNA will recruit the endonuclease RNase H), hinder translation (combine with mRNA initiation reaction site), inhibit miRNA function (indirectly up-regulate gene expression), change splicing (affect the spliceosome's splicing position on pre-MRNA), and result in other effects. The Market of RNA therapyrnAccording to the analysis report of EvaluatePharma and BCG, the global macromolecule and biotech therapy market is estimated to be 430 billion USD in 2024, among which the market size of RNA therapy will reach 8.6 billion USD in 2024, with an average annual compound growth rate of 35%. It is important to note that this BCG report was released between 2018 and 2019, and the impact of the COVID-19 epidemic could not be foreseen at that time. Nowadays, in the field of COVID-19 mRNA vaccine alone, Pfizer expects that the sales of its BioNTech COVID-19 vaccine in 2021 will be between 15 billion and 30 billion USD. Moderna announced as early as February 2021 that the total amount of orders delivered that year had reached 18.4 billion USD. Therefore, the value of the market size given by BCG is not that referential. But one thing is still worthy of reference, that is, antibody drugs have developed to a relatively mature stage, and RNA therapy, gene therapy, and cell therapy are all expected to take over antibodies to become the main power of industry growth in the next one or two decades. In terms of sales scale, RNA therapy is temporarily in a leading position under the COVID-19 epidemic. In terms of the number of approved products, according to Informa's data, 16 products of gene therapy and genetically modified cell therapies have been approved currently, while 15 RNA therapies have been approved, accounting for about 50%. From the perspective of R&D, there are about 1,840 gene therapies and genetically modified cell therapies (from pre-clinical to pre-registration), and about 630 RNA therapies that account for about 25%. The potential of RNA therapy cannot be underestimated.