Once troubled RNAi technology will eventually make a comeback

Text: Zhang Hu

Recently, transactions in the RNAi field have been active

On November 18, Novo Nordisk announced the acquisition of Dicerna for US$3.

As multinational pharmaceutical companies continue to deploy RNAi head companies, this once troubled technology will eventually make a comeback

RNAi mechanism

RNA interference (RNAi) is a biological process in which RNA molecules participate in the sequence-specific inhibition of gene expression by double-stranded RNA through translational or transcriptional inhibition

Two types of small ribonucleic acid (RNA) molecules—microRNA (miRNA) and small interfering RNA (siRNA)—are at the heart of RNA interference

The RNAi pathway exists in many eukaryotes, including animals, and is initiated by the enzyme Dicer, which cleaves long double-stranded RNA (dsRNA) molecules into short double-stranded fragments of approximately 21 nucleotides of siRNA

Figure 2.

RNAi and the Nobel Prize: There are successes and regrets

On October 2, 2006, Stanford University professor Andrew Z.

2006 Nobel Prize in Medicine and Physiology

Subsequently, three scientists including the School of Biotechnology of the University of Cambridge in the United Kingdom expressed to the famous British magazine "Nature" that they regretted that scientists in the field of plant RNAi research were not included in the Nobel Prize for RNAi, and believed that this was a "grave" error" (serious error)

Industry leader:

Alnylam Pharmaceuticals

Currently, 4 RNAi drugs have been approved by FDA or EMA, namely: Onpattro (patisiran), Givlaari (givosiran), Lumasiran (Oxlumo) and Inclisiran (Leqvio)

Without exception, the above four drugs that have been approved for marketing are all developed by Alnylam and its partner companies

Founded in 2002, Alnylam focuses on four areas: genetic diseases, liver infectious diseases, cardiometabolic diseases and central nervous system/ophthalmic diseases

Alnylam conjugated siRNA to N-Acetylgalactosamine (GalNAc) to form GalNAc-siRNA conjugates, in which GalNAc ligands can bind to the Asialoglycoprotein receptor (ASGPR) expressed by hepatocytes and targeted delivery of siRNA to hepatocytes

In order to improve the efficiency of gene silencing, Alnylam also used enhanced stabilization chemistry (ESC) technology to make some modifications to the RNA strand, and developed the ESC+ GalNAc-siRNA platform technology accordingly

Alnylam R&D pipeline

Another giant, Dicerna:

Extensive cooperation with MNC

Founded in 2006, Dicerna is a Cambridge, Massachusetts-based company dedicated to the use of RNAi to treat disease

Dicerna's proprietary RNAi technology platform, called GalXCTM, silences disease genes in the liver

In 2018, Dicerna partnered with Alexion to co-develop subcutaneously delivered GalXC RNAi molecules targeting two complement pathway targets for the treatment of complement-mediated diseases
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Dicerna is also working closely with Eli Lilly to develop new medicines in cardiometabolic disease, neurodegeneration and pain using the GalXCTMRNAi technology platform
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summary

In China, leading companies in the field of RNAi include Sirnaomics, Ribo Bio, and Genkey Gene
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Sirona Pharma utilizes pluripotent siRNA cocktail design and nanoparticle-enhanced therapeutic delivery to treat diseases, including anti-fibrosis and cancer therapy
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Genkey Gene is mainly an RNAi service provider, providing RNAi product production and R&D services
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Domestic RNAi therapy is still in its infancy.
In addition to STP705, a dual-target inhibitor based on small interfering nucleic acid from Sirona Pharmaceuticals, which is undergoing clinical trials in various diseases including cholangiocarcinoma, hepatocellular carcinoma and primary sclerosing cholangitis, The rest are still in the blank stage
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RNAi technology specifically targets mRNA and modulates protein expression, and has great potential for silencing disease-related genes
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Although the current RNAi therapy still faces many challenges in the process of clinical translation, we have reason to believe that with the continuous iteration of delivery vehicles or binding vehicles, the development of safe, precise and efficient delivery platforms will play an important role in promoting RNAi therapy.

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