1.RNAi therapeutics

RNA interference (RNAi), based on a post-transcriptional gene silencing mechanism, was found in the C. elegans antisense RNA suppression experiments by Andrew Z. Fire and named RNA interference in 1998. RNAi was named as one of the top ten scientific discoveries by Science magazine in 2001. Since then, siRNA has received widespread attention as a gene therapy drug. In 2006, Andrew Fire and Craig C. Mello won the Nobel awards in Physiology and Medicine for discovery of RNAi mechanisms. It implicates that the significance of RNAi in therapeutics for a variety of diseases. Since then, major multinational pharmaceutical companies have also stepped into this field.

In early clinical trials, most of the siRNAs were targeted directly to tissues without any delivery vehicle. Since siRNAs were too fragile and prone to degradation in the plasma，it was very difficult to ensure that siRNAs reached the target cells in the tissues. It was far more difficult to deliver siRNA than researchers originally thought. Around 2010, almost all of multinational pharmaceutical giants withdrew from the field, and siRNA research momentum had encountered obstacles. In principle, RNAi technology can prevent the synthesis of proteins by silencing targeting genes, and be applied to most therapeutic area. RNAi is expected to be a new treatment for viral hepatitis, AIDS, cardiovascular metabolic diseases and tumors. It is firmly believed that the creative opportunities will bring great value to the pharmaceutical industry.

Like genetically engineered drugs, it took dozens of years of developments from the birth of DNA recombinant technology in 1972 to Recombinant Interferon of Lilly US on the market in 1982. The monoclonal antibody-hybridoma technology was discovered in 1975, the application of antibody treatment of lymphoma was performed in 1982. Treatment of renal allograft rejection of the mouse anti-Ortholone OTK3 was on the market in 1986. 10 years later in 1996, the global monoclonal antibody market was still less than 1 billion US dollars. The world's first full-source monoclonal antibody, listed as Adalimumab (Adalimumab, treatment of rheumatoid arthritis), approved by US FDA in 2002, is currently the best-selling drugs in the world, with annual sales of tens of billions of dollars. Fluctuation of study of RNAi from the early enthusiasm to the low point of 2010 was actually normal process. Some companies gave up, and some companies stuck around, such as Ionis, Alnylam and Arrowhead in the United States. With continuous improvements of gene sequencing technology and siRNA delivery technologies, drug development of RNAi therapeutics gradually recovered from its low point, was in full swing in recent two years.

Now a considerable number of drugs have entered the clinical research stage for various diseases such as anti-virus, anti-tumor and skin diseases. The huge prospects for development have attracted many multinational pharmaceutical giants. Roche reached a $392 million RNAi drug deal with Isis in early 2013 and paid $ 450 million to acquire Santaris, a Danish RNAi professional research firm, in early 2014. Sanofi paid  $700 million for 12% of Alnylam in 2014. In April 2015 AstraZeneca showed interests in the American Regulus company, a company focused on RNAi class drug development. In addition to AstraZeneca, major pharmaceutical companies such as GSK and Sanofi also worked jointly with Regulus in the development of RNAi drugs. In November 2016, Bristol-Myers Squibb (BMS) reached a deal with Nitto Denko of Japan to develop a siRNA class of anti-fibrotic drugs, and paid an initial fee of $100 million. In March 2017, Alexion paid $7.5 million for Arbutus' LNP delivering system for RNAi drugs.

Onpattro ™ (patisaran), jointly developed by Sanofi and Alnylam, is the first-of-its-kind RNAi-based drug dedicated for the treatment of polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults, which is a milestone for the development of siRNA drugs. In October 2018, Janssen Pharmaceuticals of Johnson & Johnson and Arrowhead reached an agreement of $3.7 billion in siRNA drug development. At this stage, it is known as the industrialization blowout stage of siRNA drugs. It is believed that siRNA drugs will open a new era in the pharmaceutical industry in the near future.

2.Difficulties and key technologies of siRNA medicines

Difficulties in RNAi therapeuticare that siRNA is unstable, prone to degradation in blood and tissues, and can not stably enter target organs. The key technology for siRNA drug development is to stabilize siRNA, cross the cell membrane barrier, and resistant to degradation before reaching the target cell. An efficient delivery system protects siRNA from degradation and delivers siRNA to target cells. A variety of RNAi therapeutic drugs can be developed based on the RNAi drug delivery platform.