nucleic acid drugs change the treatment methods of diseases
With the continuous development of molecular biology technology , the relationship between gene mutations and diseases has gained more and more in-depth understanding, and nucleic acid drugs have also attracted much attention due to their huge application potential in disease diagnosis and treatment. Nucleic acid is the general term for DNA and RNA, where DNA is the material basis for storing, copying and transmitting genetic information. RNA plays an important role in protein synthesis. We usually call drugs that use DNA as the carrier or manipulation object gene drug , and drugs that use RNA as the carrier or target object are called nucleic acid drugs. Nucleic acid drugs can directly target pathogenic genes or mRNA to cure diseases at the molecular level. Compared with traditional small molecule drugs and antibody drugs, nucleic acid drugs can fundamentally regulate the expression of pathogenic genes, and have obvious advantages such as simple design, short R&D cycle, strong target specificity, wide range of treatment areas and long-term effectiveness. Currently, it is widely used in the treatment of genetic diseases, tumors, viral infections and other diseases, and is one of the most promising areas in the research and development of biomedical today.
Figure 1: Central rule content diagram
nucleic acid drugs era has arrived, and blockbuster products have been launched one after another
Since the first nucleic acid drug Formiweisen sodium was launched in 1998, the development speed of nucleic acid drugs has also accelerated in recent years. Several potential blockbuster drugs have successively released clinical data or been approved for clinical treatment. In 2018, the world's first siRNA drug (Patisiran) was approved, and it was the first nucleic acid drug to adopt the LNP delivery system; from 2018 to 2020, there were 4 siRNA drugs and 3 ASO drugs approved (FDA and EMA); in 2020, one of the world's first vaccines to enter clinical trials, mRNA-1273, which took only 27 days from the release of the gene sequence to the preparation of the first batch of samples. At present, there are 16 nucleic acid drugs approved for marketing around the world, including 14 small nucleic acid drugs (of which 3 have been delisted) and 2 mRNA vaccines. Covering the fields of antiviral, antitumor or cardiac and metabolic diseases, liver diseases, and a variety of rare diseases, , etc., the commercialization of small nucleic acid drugs and mRNA vaccines has promoted the wave of nucleic acid drug research and development, and nucleic acid drugs are expected to become the third largest type of drug after small molecule drug and antibody drugs.
Figure 2: Marketed nucleic acid drug
nucleic acid drug major overseas transactions in the past five years
nucleic acid drug has gradually developed its huge therapeutic potential and presented broad market prospects with its unique advantages. Mergers and acquisition transactions in the field of nucleic acid drugs and product authorization introduction cases are also actively carried out. Many large multinational pharmaceutical companies are targeting their huge market space and development potential, including Johnson & Johnson , Novartis , Sanofi , Takeda , Eli Lilly, etc., actively driving the development of the nucleic acid field through cooperative research and development, equity introduction and other methods.
Figure 3: Major overseas transactions of nucleic acid drugs in the past five years
not only sells overseas, but also set off a boom in investment and financing.
The industry prospects are attractive, and more and more entrants are entering the market. According to statistics, in 2021, there were 29 investment and financing events in the field of nucleic acid drugs in my country, an increase of 17 from 2020, and the investment and financing amount reached 12.912 billion yuan, an increase of 8.256 billion yuan from 2020. At the same time, from 2021 to the beginning of 2022, 22 nucleic acid drug companies in my country completed financing. For example, Aibo Biotech, which focuses on mRNA vaccine research and development, completed three rounds of financing in 2021, with a total financing amount of more than US$1 billion; Si Microbiology completed a financing of 1.2 billion yuan in June 2021, creating the largest single financing record in the field of mRNA drug research and development in China; Shengnuo Pharmaceutical, which focuses on RNA therapy research and development, was listed on the main board of the Hong Kong Stock Exchange on December 30, 2021, becoming the "first nucleic acid drug stock in China."
Figure 4: Major overseas transactions of nucleic acid drugs in the past five years
Innovation in key technologies, promoting the development of nucleic acid drugs
Nucleic acid drugs have obvious advantages such as high specificity, high efficiency, and long-term effectiveness. The research and development of nucleic acid drugs has gone through a long process, but with many advantages and accelerated development, nucleic acid drugs also face various challenges:
- is the development of carrier to ensure the stability of RNA during nucleic acid transport, and nucleic acid drugs reach target cells/target organs;
- is the improvement of the drug delivery system, how to improve the drug delivery system can achieve the same effect using low doses.
The development of any new therapy must be accompanied by technological breakthroughs, and "Whoever masters the core technology can have a strong moat." Among them, key technologies such as chemical modification and delivery system technology play a crucial role in improving the above defects.
Chemical modification of nucleic acid drugs
Exogenous nucleic acid drugs need to overcome many obstacles to enter the body and play a role. These obstacles have also caused difficulties in the research and development of nucleic acid drugs, but with the development of new technologies, some problems have already had better solutions. Chemical modification can enhance the ability of RNA drugs to resist the degradation of endogenous endonuclease and exonuclease , greatly improving the efficacy of the drug. For siRNA drugs, chemical modifications can also enhance the selectivity of their antisense strands to reduce off-target RNAi activity and alter physical and chemical properties to enhance delivery capabilities. Chemical modification mainly includes the modification of the 2-position hydroxyl group (2’OH) of the sugar to methoxy (2’OMe), fluorine (F) or (2’MOE); or the replacement of some nucleic acid units with LNA, UNA or GNA. These modifications can successfully increase activity and selectivity and reduce off-target effects and reduce side effects. Delivery and administration of nucleic acid drugs by
nucleic acid drugs rely solely on chemical modifications to be easily degraded rapidly in the blood circulation, is not easy to accumulate in the target tissue, and is not easy to effectively pass through the target cell membrane to reach the site of action in the cytoplasm. Therefore, it is necessary to rely on the power of the delivery system, and delivery system technology is the key to ensuring the effectiveness and safety of nucleic acid drugs. It plays an important role in protecting RNA structure, enhancing targeting capabilities, reducing drug delivery dosage and reducing toxic side effects.
Currently, nucleic acid drug carriers are mainly divided into viral and non-viral vectors. The former includes adeno-associated viruses (lentivirus, adenovirus and retroviruses, etc., and the latter includes lipid vectors, vesicles, etc. Judging from the marketed drugs, the GalNAc conjugated ligation delivery system dominates small nucleic acid drugs due to its excellent targeting performance against the liver; the mRNA delivery system includes liposomes , nanoliposomes, lipid complexes, multimers , lipid nanoparticles, and exosomes. Among them, lipid nanoparticles are the most common delivery system in mRNA drugs. Exosomes are considered to have the most potential to solve the bottleneck of delivery of small nucleic acid drugs in the body, because exosomes have lower immunogenicity and toxicity, better cross-cell and tissue barrier capabilities, and the potential to achieve more efficient cell delivery. At the same time, exosomes can also maintain binding to target molecules and load endogenously and synthetic RNA The possibility of cargo.
Figure 5: Representative nucleic acid delivery technology (Source "Biotechnology Advances")
nucleic acid drug, with obvious advantages and broad prospects
Although nucleic acid drugs have certain limitations, it cannot be ignored that with the continuous breakthroughs in core technologies such as chemical modification and delivery systems, nucleic acid drugs have gradually developed huge market potential to change the treatment methods of diseases.
- nucleic acid drugs can break through the limitations of protein drug properties of small molecule drugs and antibody drugs targets, and have unique advantages. The field of indications is constantly expanding, small nucleic acid drugs are expanding from genetic diseases to chronic diseases, mRNA drugs are expanding from preventive infectious vaccines to tumor therapeutic vaccines and protein replacement therapy
- nucleic acid drugs have many potential indications, and there are huge unmet clinical needs
- nucleic acid drugs. Technology innovation, favorable policies and active capital, helping China's nucleic acid drug industry flourish.
Generally speaking, the development of the nucleic acid drug industry is in full swing, and the development and exploration of domestic nucleic acid drugs is also very promising. It is the type of drug that is most likely to enter the leading state from the side-by-side state. Let us welcome this new era of nucleic acid drugs together.
September 27, 2022 , ProteinSimple and the Pharmaceutical Merger Circle jointly held a nucleic acid drug research and development and innovation seminar, which will focus on discussing the development ideas of nucleic acid drugs, CMC of nucleic acid drugs, and clinical development of nucleic acid drugs. Visiting professor of nanomedicine and immunology at Harvard Medical School, professor of Sichuan University, co-founder of Chengdu Weisjin Biotechnology Dr. Song Xiangrong , Chief Technology Officer of Venucia Biotechnology, and Professor Hao Dianming, Marketing Manager of ProteinSimple, were invited to participate. hopes to inspire the industry.
About ProteinSimple
ProteinSimple is an industry-leading protein analysis brand under the Bio-Techne Group (NASDAQ:TECH), a listed company in the United States. We are committed to developing and producing more accurate, faster and more sensitive innovative protein analysis tools, including protein charge characterization, protein purity analysis, quantitative detection of protein post-translation modification, protein immunity experiments such as Western and ELISA quantitative detection of protein expression, etc., to help scientists in the fields of vaccine research and development, biopharmaceuticals, cell therapy, gene therapy, biomedical and life sciences to solve protein analysis problems and deeply analyze the relationship between proteins and diseases.
About Yaorong Circle
Yaorong Circle PRHub aims to help biomedical technology enterprises to promote brand and business expansion services, formulate systematic solutions to customers' real needs, and use "translation-dimensionality reduction-scenario" to inform the public in a straightforward and easy-to-understand way. At the same time, the cooperation purpose is achieved based on the traffic channel covering 1 million+ vertical users, and help partners complete the closed-loop marketing service from brand to business end. We have completed dozens of offline biomedical research and development conferences with a scale of 1,000 people, covering small-molecular new drugs, large-molecular new drugs, improved new drugs, BD cross-border transactions and other fields. The brand conference includes China International Bio and Chemical Pharmaceutical Industry Conference (more than 6,000 people), Generic Drug Summit (more than 600 people), and New Drug Innovator Series Summit (more than 1,200 people), and serves more than 100 listed/unicorn/biotechnology/pharmaceutical companies.
Pharmaceutical Rong Circle Biopharmaceutical Ecosystem Partners: Lingkai Pharmaceutical, Fukang Pharmaceutical, Hanrui Pharmaceutical, Jianyuan Pharmaceutical, Jimin Kexin, Shenzhen Huarong, Zezheng Pharmaceutical, Zhongke Pureshen, Arthur Pharmaceutical, Suzhou Yake, Qingmu Pharmaceutical, Sunshine Demei, Chengdu Pioneer, Fangda Pharmaceutical, Baicheng Pharmaceutical, Huize Pharmaceutical, Jianran Laboratory, Thermofei , Metler, Suzhou Jingyun, Kangribaio, Yiming Cell, Zhuhai Yisheng, Greentech, Sanyou Biological, BaioSaitu, Hangzhou Haoyang, Shenji Bio, Kingsrui Pengbo, AisiPu, Nanjing Life Energy, ProteinSimple, Hanku Pharmaceutical, Shandong Chuancheng Pharmaceutical, Shandong Nuomingkang, Hansi Bio, Maiwei Bio , Zhuoya Pharmaceutical, Jiashu Medical, Jingtai Technology, Yingsi Intelligent, Hengxing Pharmaceutical, Huayi Pharmaceutical, Guangzhou Diqi, Inokai, Yinggu Information...
References
[1] Kulkarni, J.A. et al. “The Current Landscape of Nucleic Acid Therapeutics.” Nature Nanotechnology, 2021,16(841):630-643.
[2] "Biotechnology Advanceds"
[3] Lianxiao Liu et al. “Therapeutic Mechanism of Nucleic Acid Drugs.” Medicinal Chemistry & Drug Discovery, 2021, 6, 903 –916
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