A "switch" for safer gene therapy

Researchers at the Cima Universidad de Navarra have identified a ribonucleic acid (RNA) that could be used to modulate gene therapy against cancer and other pathologies. These results guide the development of personalized treatments for each patient and at different stages of their disease.

Cells evolve to produce thousands of different RNAs that bind to proteins, DNA regions or other RNAs to perform different functions. For example, RNAs can contribute to the formation of tumor cells. "Our study has been able to mimic this natural evolution in the laboratory to identify synthetic RNAs that, when introduced into the cell, are able to control the expression of a therapeutic gene," explains Dr. Puri Fortes, director of the RNA Biology Program at Cima and co-director of the study with Dr. Fernando Pastor.

In general, therapeutic genes should always be beneficial to the patient. However, they sometimes cause unwanted side effects that lead to toxicity. Until now, it has been very difficult to modulate gene expression to prevent possible side effects. "At Cima we have identified an RNA sequence that acts as a regulator that modulates the expression of the therapeutic gene. Under normal conditions, when the therapy is introduced into the patient, the switch is turned off and the gene is not expressed, there is no effect," the researchers explain. "When the physician considers it appropriate, he will give the patient a conventional antibiotic. This will bind to the engineered RNA sequence and 'turn on' the gene to produce the therapeutic protein. If the physician or patient notices any unwanted effects, the antibiotic can be stopped and the gene will be turned off. If conditions change, the gene can be turned on again, using the antibiotic, as many times as necessary," they explain.  

One of the treatments that can benefit from this type of "gene switch" is CAR-T, which involves modifying these immune system cells so that they are able to attack tumor cells. "Sometimes CAR-T cells produce unwanted effects that would disappear with this strategy," Drs. Fortes and Pastor point out.

The results of this work have been published in ACS Nano, a scientific journal of the American Chemical Society.

Applications in various disciplines

One of the main conclusions of the work is that it guides the clinician in applying the best approach for each case. As Dr. Pastor explains, "this RNA opens and closes in response to the antibiotic and allows us to regulate gene expression not only for CARTs but also for other therapies that at a certain moment cause collateral side effects".

A very interesting application of this type of switch is the large-scale production of recombinant proteins for therapeutic purposes. "This switch would allow us to induce the production of the protein at the optimal time, to achieve the highest yield of therapeutic protein synthesis. In this line, future studies are going to be carried out in collaboration with the Navarre recombinant protein company 3P Biopharmaceuticals."  

From now on, the study will focus on determining the application of this system in various gene therapy approaches (both viral and non-viral) using different drugs available in medical practice.

This work, carried out in the framework of the Centro de Investigación Biomédica en Red (CIBER), together with the Instituto de Investigación Sanitaria de Navarra (IdiSNA), has received funding from the "la Caixa" Foundation, through the CaixaImpulse call for proposals.