How does RNA interfere?

A new study indicates an unexpected side effect of suppressing the formation of blood vessels, following the use of RNA, in a different mechanism than what was commonly thought until now

In recent years, the use of RNAi has emerged as the next promise in the design of safer drugs, capable of silencing proteins involved in serious diseases. A new study indicates an unexpected side effect of suppressing the formation of blood vessels, following the use of RNA, in a different mechanism than what was commonly thought until now.

The RNA molecules are mainly known for their function as a kind of messenger (mRNA), which is similar in structure and composition to DNA, and links between the genetic information encoded in DNA and the protein products that build the cells and enable their activity. happening in the cell. One of these control mechanisms is based on RNA interference (RNAi). This mechanism exists in eukaryotic cells (with a nucleus) from plants, worms to humans.

The RNAi enables the silencing of gene expression in a targeted and specific manner within the cells. This is by attaching to the mRNA molecules (which are suitable in sequence for a certain RNAi), accelerating their degradation, and preventing their translation into proteins. The publication of the mechanism of action of RNAi in flatworms about a decade ago earned Andrew Pierre and Craig Mello the Nobel Prize in Medicine and Physiology in 2006.

RNAi is of great importance as part of our immune defense system against foreign genetic elements entering the cell, such as viruses. In addition, RNAi is important in the control of genes involved in developmental processes, in the differentiation of stem cells and in the control of the cell cycle. Due to the ability of the RNAi molecules to specifically silence the expression of proteins, including those that cause cell damage, they are used as an important tool in genetic research. Today there are many studies, some of which are even in the stages of clinical trials in the use of RNAi to treat and cure various diseases, including diseases caused by viruses, neurodegenerative diseases, diabetes, retinal degeneration and treatments for various types of cancer.

A sensational discovery in the field of RNAi was published this month in the journal Nature as part of a study conducted by Prof. Jayakrishna Ambati and his partners at the University of Kentucky. The researchers examined the ability to treat and cure macular degeneration using small interfering RNA (siRNA). The siRNA molecules are a type of RNAi designed to specifically silence the target genes against which they are designed.

Retinal degeneration disease is very common, and results in severe damage to vision up to blindness. The disease is caused, among other things, by abnormal growth of many blood vessels under the retina. In an attempt to treat the disease, several clinical trials have been approved using siRNA to silence proteins involved in signaling pathways for blood vessel growth, with the assumption that the type of siRNA given in the treatment is precisely directed to a target gene.

Prof. Jayakrishna Ambati and his partners discovered that, contrary to what was commonly thought, the effect of inhibiting the growth of blood vessels by the RNA molecules when they are injected into the retinal area is not specific to the target gene against which the treatment is directed, and does not depend on the sequence of the bases from which the siRNA molecule is built. In fact, almost any siRNA sequence longer than 21 bases can prevent blood vessel growth. The researchers discovered that the RNA molecules do not enter the cells, and they affect gene expression through a mechanism that differs from the mechanism described for RNAi.

The researchers found that the RNA molecules have the ability to bind to a receptor found on the surface of the cells called TLR3 (Toll-like receptor 3). Following the link, a signal transmission chain is activated in the cell which eventually leads to the creation of proteins in the cell (IFNγ, IL-12) that inhibit the creation of new blood vessels. According to Prof. Ambati, the discovery does not contradict the mechanism of action of siRNA in specific silencing of the target gene when it enters the cells. However, following the findings, one must be aware of the general effect that siRNA has in suppressing the formation of blood vessels when it is intended for the treatment of various diseases.