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An Overview of siRNA Gene Therapy

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RNA interference (RNAi) is a revolutionary discovery in genetic research. RNAi can specifically silence endogenous or exogenous target genes, which is a rapidly developing gene control technology with broad application prospects. Since Tuchl et al. found in 2001 that artificially synthesized double-stranded small interfering RNA (siRNA) can efficiently silence the expression of target genes in mammalian cells, the life science field has set off a wave of basic and applied research on siRNA. With the gene silencing mechanism, significant progress has been made in the development of siRNA drugs to treat diseases.

In August 2018, the world’s first siRNA drug, Onpattro (Patisiran) was approved by the FDA for the treatment of patients with polyneuropathy caused by hATTR.

Onpattro is the world's first drug developed based on the Nobel Prize achievement RNA interference technology. In 1998, Andrew Fire and Craig Mello revealed the RNAi phenomenon for the first time in C. elegans, and won the Nobel Prize in Physiology in 2006 for this discovery. The approval of the first siRNA drug in 2018 takes 20 years. Onpattro's approval marks a major breakthrough in the field of RNAi medicines, and small nucleic acid medicines are finally dawning.

According to statistics, among disease-related proteins in the human body, more than 80% of the proteins cannot be targeted by current conventional small molecule drugs and biological macromolecular preparations, and are non-drugable proteins. Gene therapy aimed at treating diseases through gene expression, silencing and other functions is considered by the industry as the third generation of therapeutic drugs after chemical small molecule drugs and biological macromolecular drugs. This kind of therapy achieves the treatment of diseases at the genetic level, not restricted by non-drugable protein. As the most mainstream type of RNA drugs in gene therapy, siRNA drugs are used to treat diseases from the level of mRNA. Compared with chemical small molecular drugs and biological macromolecular drugs, they have a higher efficiency at the protein level.

In 2004, Bevasiranib, an siRNA drug developed by Opko in the United States, launched a clinical trial for the treatment of wet age-related macular degeneration. This is the first clinical trial related to siRNA in the world. Subsequently, many global pharmaceutical giants, including Pfizer, Sanofi, Roche, and Merck, joined the development queue of siRNA drugs.

Unfortunately, the development of the Bevasiranib project has failed in phase III due to poor clinical results, and other latecomers have not been spared. The reason is that the poor targeting, off-target effects and stability of RNAi drugs are the most important constraints that affect their efficacy. Many factors have led to the efficacy of these drugs being far less than expected, but also accompanied by serious insurmountable medication side effect.

From the perspective of technical requirements, siRNA after intravenous injection is easily degraded by nucleases, has high renal clearance, poor cell uptake efficiency, and clinical application is limited. The success of siRNA drugs depends on the development of drug delivery system technology, especially the ability to delivery carrier technology that transports RNAi safely and efficiently to specific therapeutic targets in the body.

As the world's first approved siRNA drug, Patisiran adopts the LNP drug delivery system to encapsulate RNAi drugs in liposomes, which can be administered by intravenous injection. The liposome coating greatly improves the stability of the drug and the targeting of liver tissue can ensure that the siRNA will not be filtered by the kidney and will be gradually taken up by the target cells of the liver tissue during the blood circulation. This is the key to Patissiran to overcome the above major constraints and get approved for marketing.

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