Bringing New Therapeutic Options to Cancer and Rare Diseases

Many causes of cancer and rare diseases are related to genetic mutations. It is difficult for small molecule and antibody drugs to address the three-dimensional structure of all target mutant proteins, and many genetic mutation diseases still have no cure. To provide more effective therapeutics, we need to get into the central dogma (the concept of molecular biology that DNA information is transmitted to proteins via mRNA), and nucleic acid medicine makes this possible.
Nucleic acid therapeutics can suppress a single target gene and have recently been gaining worldwide attention as a new type of medicine.
Currently, the main nucleic acid therapeutics being commercialized are siRNA and antisense, and there are five siRNA drugs. Recently, 1-2 products a year have been launched, and more products are expected to be brought to market in the future. siRNA's mechanism is based on RNA interference (RNAi), a function that is inherent in cells, and this effectively suppresses messenger RNA.

How RNA Interference Works

RNA interference (RNAi) is a mechanism by which mRNAs with complementary sequences to double-stranded RNA are specifically degraded. This discovery won the Nobel Prize in Physiology or Medicine in 2006. siRNA has the same mechanism of RNAi, degrading mRNA that has complementary sequences to siRNA reduces the production of the target protein.
Details below.

i. siRNA is taken up into the cytoplasm.



ii. The siRNA is loaded onto the Argonaute2 (AGO2) protein.

iii. On the AGO2, the base at the 5′ end of the RNA strand on the side of the double strand that is paired with the target mRNA (Guide strand) is trapped in the pocket structure of the AGO2, while the other RNA strand with a complementary sequence to the Guide strand (Passenger strand) is removed.


iv. On AGO2, target mRNAs pairs with the siRNA guide strand and is cleaved by AGO2. The cleaved target mRNA is degraded and the protein production is suppressed.

Current Status and Challenges of Nucleic Acid Medicines.

The great advantage of Nucleic acid medicines, especially siRNA, is that they can be chemically synthesized with determined sequence design methods. Furthermore, they have few side effects and can treat patients with injections just once every few months. All siRNA drugs already approved are being developed by Alnylam Pharmaceuticals Inc., a leading company in this field in the United States. All of their siRNA drugs target diseases in hepatocytes. This is because existing siRNA sequence design techniques can suppress the target genes, but cannot control the presence or absence of single nucleotide mutations in mRNA. Therefore, Alnylam takes a unique approach to drug discovery by selecting target genes and disease targets that are not affected by the suppression of both normal and mutant mRNAs.

ANRis provides SNPD-siRNA, a new sequence design method for siRNA therapeutics that can selectively suppress the single nucleotide mutant mRNAs, invented by Professor Kumiko Ui-Tei of The University of Tokyo.。

Existing sequence design methods suppress normal mRNAs, causing side effects and imposing a burden on patients. In comparison, "SNPD-siRNA," single nucleotide polymorphism-distinguishable siRNA, is an innovative sequence design method that can specifically suppress only mRNAs containing single nucleotide mutations, and was systematized after years of experimental trials.

To demonstrate SNPD-siRNA technology, we focused on KRAS, one of the 'driver genes' directly involved in cancer development and progression. We designed and synthesized SNPD-siRNA corresponding to KRAS (35th base) and conducted gene expression regulation analysis (reporter assay). It showed RNA interference effect that distinguished single nucleotide difference and specifically suppressed them. The efficacy of SNPD-siRNA was also confirmed in the planar culture of pancreatic cancer-derived cells and in mice of the xenografted model (the model that human-derived cancer cells are transplanted into immunodeficient mice).