Solving the problem of side effects of siRNA drugs for the treatment of genetic diseases.

Small interfering RNA preparations (miRNAs) are a class of therapeutic agents that suppress certain genes associated with hereditary diseases. However, there are problems with siRNA drugs, as siRNAs often drown out genes other than the target ones, causing side effects.

Using formamide, a group from Nagoya University in Japan succeeded in chemically modifying miRNA to reduce the risks of these non-targeted effects by increasing the safety of miRNA preparations for genetic therapy. The results were published in the journal Nucleic Acids Research.

siRNAs are short double-stranded RNAs. miRNAs interact with the target's information RNA (mRNA), the structure of proteins, preventing their expression. By silencing products of harmful genes, such as pathogenic proteins, miRNAs are a potential treatment for a number of genetic diseases.

However, the therapeutic potential of miRNA is limited by non-target effects that occur when miRNAs interact with non-target mRNA strands. These unintentional interactions can lead to harmful changes in the main genes, disrupting cellular processes and weakening the immune response.

A significant cause of these non-targeted effects is the area of seven nucleotides, known as the seeding area, located inside the miRNA guide chain, which is crucial for target recognition. Non-target effects often occur, since the sequence of the seeding area forms pairs of bases with non-target mRNA filaments.

"The non-target effect probably occurs when there are non-target mRNAs that form base pairs with the embryonic region of miRNA," explained Professor Hiroshi Abe. "We realized that the non-target effect can be suppressed by reducing the mating capacity of the bases or the stability of the double-chain chain in this seed region by chemical modification, ensuring that a stable complex is formed only when the entire guide chain binds to the target mRNA. "

The group led by Professor Abe and his student Kohei Nomura used a modification of the formamide to modify the miRNA in this important region. Foramide groups can inhibit the formation of hydrogen bonds.

In mRNA, hydrogen bonds between complementary bases are necessary for the stability of the double helix. Formamide interferes with these hydrogen bonds, which leads to destabilization of the spiral structure of mRNA, causing denaturation or separation of chains. Without chain formation, binding to the embryonal region of miRNA is difficult, which reduces the risk of non-targeted effects.

"This modification made it possible to suppress non-target effects with higher efficiency than existing chemical modifications," Abe said. "The introduction of modification in one place achieved the desired effect, allowing to create a very flexible sequence of miRNA."

It is expected that chemically modified miRNAs using this modification will be used as miRNA preparations with fewer side effects. Nomura believes that the study has a potential use as a siRNA drug for the treatment of diseases such as hereditary transthyretin amyloidosis, acute hepatic porphyria, primary hyperoxaluria type 1, primary hypercholesterolemia and mixed dyslipidemia.