Therapeutic RNAs have learned to deliver to cells by ultrasound
Oleg Lischuk, N+1
American scientists have managed to deliver RNA molecules into the intestinal mucosa of live mice using ultrasound. The results of the work are published in the journal Gastroenterology (Schoellhammer et al., Ultrasound-Mediated Delivery of RNA to Colonic Mucosa of Live Mice).
The delivery of RNA into cells allows to regulate their functions, which are disrupted in various diseases. Depending on the type of RNA, it is possible to start the synthesis of the desired protein in the cell or to influence the expression of a gene. At the same time, it is very difficult to deliver nucleic acid into the cell due to the large size of the molecule. The work is also complicated by the presence of nuclease enzymes that rapidly cleave RNA.
Employees of the Massachusetts Institute of Technology and Boston Children's Hospital have previously discovered that the permeability of intestinal cell membranes for small drug molecules can be increased by using the effect of unsteady cavitation. It consists in the fact that under the action of ultrasound with the specified parameters, small bubbles form in the liquid, which quickly collapse and "push" the molecules into the cell. Scientists decided to find out whether such a method is suitable for delivering macromolecules, in particular RNA, to cells.
In the experiment, they used a mouse model of irritable bowel syndrome, a severe chronic inflammatory disease of the colon. Animals were injected with an enema solution of small interfering RNAs (miRNAs) that block the translation of matrix RNA (mRNA) of one of the most important mediators of inflammation — tumor necrosis factor alpha (TNF-α). At the same time, the solution was affected by half-second ultrasound pulses with frequencies from 20 to 100 kilohertz.
As a result, the production of TNF-α in the colon mucosa decreased by 7-10 times, which almost completely eliminated its inflammation. The mice tolerated the procedure well, despite the acute inflammatory process. The introduction of miRNA without exposure to ultrasound had no effect.
After that, the researchers conducted an experiment with larger molecules. They injected mRNA encoding the enzyme luciferase and its substrate D-luciferin into the intestines of mice. When oxidized by luciferase, luciferin emits visible light (this phenomenon is called bioluminescence). Under the influence of ultrasound, mRNA and luciferin penetrated into the cells, which began to synthesize luciferase and glow. The intensity of bioluminescence of the intestinal mucosa when using ultrasound was 11 times greater than without it.
Having obtained similar results, the scientists created the company Suono Bio for further development, clinical trials and commercialization of the technology. Currently, they are working on the creation of capsules for oral administration, which contain both a given RNA and a source of ultrasonic pulses. Such a device should save doctors and patients from the need to use enemas and rectally administered ultrasound generators.
Small interfering RNAs belong to a large family of non-coding RNAs that do not directly participate in protein synthesis on the DNA matrix, but are important regulators of many intracellular processes and take part in the development of various diseases.
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23.01.2017