Paolo Rossi Castelli 8 July 2021 6 min read

Genetic “bullets” against cystic fibrosis

An experimental treatment is being analysed at the University of North Carolina. Small molecules called oligonucleotides appear capable of repairing some of the damage caused by the illness.

An innovative strategy developed by researchers of the University of North Carolina at Chapel Hill seems to give new hope to those affected by cystic fibrosis, a genetic disease chiefly affecting the lungs (as well as the intestine and other organs) and which is very hard to treat.

As science magazine Nucleic Acids Research now reports, the American researchers have homed in on small molecules called oligonucleotides (fragments of genetic code), which can be used to literally repair the damage this disease causes (treatments currently available can instead only act on the symptoms and associated infections).

What is cystic fibrosis?

Let’s begin at the beginning. Cystic fibrosis is caused by a series of anomalies in a protein called CFTR, which is vital for allowing chloride to pass between the cell membranes, and more generally for the production of mucous (the viscous liquid which ensures the cells in lungs and other organs function properly).

Those who possess genetic mutations that cause the CFTR to work poorly (more than 1,500 possible mutations have already been catalogued, and they can be inherited from both parents) cannot produce enough mucous, causing problems which can become very serious, particularly for the lungs, with considerable knock-on effects on quality of life.

The mucous dries out, becoming thick, hard to expel and highly susceptible to bacterial infection.

For some years now, drugs have been available which attempt to “remodulate” the altered CFTR protein to make it more efficient. Yet they are not effective in all patients: particularly those (at least 13% of the total) affected by a genetic defect called splicing.

Splicing, a problematic genetic defect

What does it mean? Splicing is the “cutting and stitching” which cells carry out to synthesise proteins according to the instructions contained in DNA and messenger RNA (a sort of “mould” of the DNA).

If the splicing doesn’t occur properly (it takes very little to alter these operations), the proteins produced are defective, leading to issues which can become serious, such as in the case of cystic fibrosis.

For some years now, attempts have focused on getting the suitably programmed oligonucleotide molecules mentioned earlier to the cells so they can “correct” the splicing.

“But it is extremely difficult to achieve significant concentration levels of oligonucleotides in the lungs,” explains Silvia Kreda, associate professor of the Medicine Department at University of North Carolina at Chapel Hill.

This occurs, we would add, when the therapeutic oligonucleotides are injected into the blood; they end up becoming trapped in the numerous protective systems which the body activates to block viruses and other undesirable molecules.

Accordingly, even when the oligonucleotides manage to get into the cells, like “genetic bullets”, they almost always become trapped inside vesicles called endosomes and expelled. Alternatively, they are degraded by the enzymes before they can perform their task.

A new experimental technique

Professor Kreda and her colleagues have developed a new technique to overcome these issues by adding other small molecules, capable of deactivating the body’s natural defences, to the oligonucleotides. Laboratory experiments carried out thus far on a culture of lung cells from a cystic fibrosis patient (who has the splicing defect) have yielded excellent results. Researchers now intend to continue their work and will also conduct clinical experiments on patients. This study is backed in the United States by the Cystic Fibrosis Foundation and the National Institutes of Health.


Paolo Rossi Castelli

Journalist since 1983, Paolo has been dealing with scientific divulgation for years, especially in the fields of medicine and biology. He is the creator of Sportello Cancro, the site created by on oncology in collaboration with the Umberto Veronesi Foundation. He collaborated with the pages of the Science of Corriere della Sera for several years. He is the founder and director of PRC-Comunicare la scienza.