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Genetic scissors in the fight against RNA viruses

Genetic scissors in the fight against RNA viruses

Despite the efficacy of SARS-CoV-2 vaccines, new variants of the virus require searching for other ways of preventing new infections. Genetic vaccines are already proving to be helpful, whether it be th mRNA-based Pfizer-BioNTech and Moderna vaccines, or the DNA-based AstraZeneca and Johnson & Johnson vaccines.

In response to new viral variants, scientists are able to relatively quickly modify nucleic acid sequences in available vaccines, increasing the chance of the organism producing antibodies that fight off the spike protein encoded by the altered gene of the new variants of SARS-CoV-2. However, an innovative method may help us to combat viruses and reduce their multiplication in a new way.

Recognising the sequence of a target nucleic acid, DNA, by its complimentary RNA sequences (called crRNA: CRISPR-RNA) is the basis of gene edition using the Cas9 nuclease. This technique, also known as ‘genetic scissors’ or, more formally, CRISPR-Cas9, allows for precise modification of cell genome, and has earned its discoverers, Emmanuelle Charpentier and Jennifer Doudna, the Nobel Prize in Chemistry in 2020. Gene editing is already being tested as treatment for conditions such as blood diseases, like b-thalassemia and sickle cell disease. Nevertheless, the Cas9 nuclease can only cleave through DNA, while SARS-CoV-2, like most human viruses, functions based on RNA. To fight them, we need to make use of other types of Cas enzymes, such as the Cas13a nuclease originating from the Leptotrichia buccallis bacterium. The enzyme as well as its variants do not cleave DNA, but rather single-stranded RNA. Therefore, using Cas13 on specific RNA sequences, such as those in SARS-CoV-2, can cause it to degrade, preventing the infection of new cells and, consequently, the progression of COVID-19.

In a paper published recently in Nature Communications, a team led by Mohamed Fareh in collaboration with other researchers supervised by Joseph Trapani from the University of Melbourne has described the possibility of digesting SARS-CoV-2 RNA through the use of specially designed crRNA sequences. What is more, the researchers have designed the crRNA in such a way that was able to recognise a specific RNA fragment even if it featured changes in some of the nucleotides – a phenomenon that is typical in the emergence of new virus variants. This provides an opportunity to develop special cocktails of crRNA particles that would fight off not only the spike protein, but also other SARS-CoV-2 RNA sequences. The techniques used by the researchers to introduce crRNa and Cas13a nuclease have effectively reduced the multiplication rate of SARS-CoV-2 in human cells in laboratories, including respiratory epithelium cells.

Naturally, in vitro studies are just the beginning, but it is necessary to develop safe and effective ways of administering this new type of drugs to patients. To that end, animal testing is necessary. And scientists are already working on that. In another paper, this time published in Nature Biotechnology, researchers from the Georgia Institute of Technology and Emory University in Atlanta have proven that it is possible to curb the replication of the flu virus in mice and SARS-CoV-2 in hamsters. The project, supervised by Emmeline Blanchard, Chiara Zurla and Philip Santangelo, involved administering specially prepared mRNA particles of the Cas13a nuclease and crRNA targeting sequences as aerosol into the lungs of mice that have been previously infected with the flu. They managed to inhibit the progression of the disease. In the case of hamsters, a different strategy was employed: first, the animals inhaled an aerosol containing crRNA and Cas13a-encoding mRNA, and then they were infected with SARS-CoV-2. The researchers observed that Cas13 has reduced the number of viral particles by half and prevented the animals from losing weight (which is an indicator of the development of an infection).

Research suggests that this strategy can be further studied and developed with the aim of using it on people. In the case of SARS-CoV-2, it will surely require testing on specifically selected animal models, such as transgenic mice exhibiting human expression of the ACE2 receptor, which is used by the virus to access our cells (ordinary mice are not vulnerable to this type of virus).  It will also be necessary to test out various combinations of crRNAs in order to programme Cas13 to target different SARS-CoV-2 genes and check whether the designed particles can recognise new variants of the virus. The contents of the former of the abovementioned papers give us hope that this is true.

The possibility of developing a new, specific group of drugs that would help us fight not only COVID-19, but also other viral infections, is of great importance. As stated in the paper published in Nature Biotechnology, out of 219 known human viruses, as many as 214 are RNA-based. Although viral infections make up about 6.6% of global deaths, we only have about 90 registered anti-viral drugs that are effective against nine types of viruses. Moreover, the available vaccines can protect us from only 15 species of viruses. In this light, innovative therapies based on molecular biology and developing vaccines and other drugs that can be quickly modified in case of new variants are a much needed help. As pointed out by another study and computer analyses, a few carefully selected crRNAs could be used to combat 90% of known coronaviruses, though it would, of course, be required to fully test both the safety and efficiency of this method, since, as a foreign body, it could trigger the organism’s immune response. Administering a localised and temporary active mRNA encoding this enzyme, as in the case of the paper published in Nature Biotechnology, may restrict the scope of ‘genetic scissors’ that digest viral RNA to upper respiratory tract cells, reducing the spread of infection. We can surely expect to hear more about this interesting research in the near future. It may turn out that different variants of the Cas13 protein (the studies mentioned focused on Cas13a, but there are others that tested the effectiveness of Cas13b and Cas13d against flu) will be proven safer and more effective.

Incidentally, members of the Jagiellonian University academic community will be able to learn much more about the capabilities of the CRISPR-Cas systems from Prof. Virginjus Siksnys from the University of Vilnius, who significantly contributed to their development. On 23 September, Prof. Siksnys will deliver a plenary lecture that will open the Jubilee Conference of the JU Faculty of Biochemistry, Biophysics and Biotechnology. We advise the readers to follow the latest news related to treating viral infections, and get vaccinated against COVID-19 and the flu if they have not yet done so.

Original text: www.nauka.uj.edu.pl

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