Gene editing allows a person’s genome to be rewritten to correct errors that cause diseases. This is what has been achieved with sickle cell anemia, a disease caused by a mutation that causes red blood cells to be sickle-shaped instead of the usual round one. This deformation prevents them from circulating well through the blood vessels, causing severe pain and premature death. In December 2023, the United States approved the first treatment for this hereditary disease made with the CRISPR editing system. These molecular scissors make it possible to replace the defective gene that produces hemoglobin, the protein that transports oxygen in the blood, with one that works correctly.
This technology already has applications ranging from hereditary genetic diseases to cancer immunotherapy, but it has some precision problems, such as cutting unwanted sequences similar to the target to be eliminated, or releasing cut DNA pieces that produce a harmful immune response for the patient or genomic instability. This Wednesday, the journal Nature publish two articles in which a new, potentially more precise genetic editing mechanism is described, with the capacity to introduce long DNA sequences into specific locations in the genome.
Researchers have used the capacity of what are known as jumping genes (or transposable genetic elements), mobile elements that can go to different parts of the genome of the cell or even other microorganisms and play an essential role in evolution and adaptation. of living beings. For their jumps through the genome, these elements use enzymes, recombinases, which build an RNA bridge between the DNA of origin and that of the place where it is going to be inserted.
According to the authors, from several academic institutions and universities including Berkeley and Stanford (USA) and Tokyo (Japan), these bridges are reprogrammable and serve to choose the specific place in which the piece of Desired DNA. This versatility would allow, for example, carrying a functional copy of a gene to replace a defective one that is causing a disease, as in the case of sickle cell anemia. In one of the works, the authors were able to carry a gene to a region of the bacteria’s genome Escherichia coli with an accuracy of 94% and an insertion efficiency of 60%.
Using this mechanism, a team led by Patrick Hsu, of the Arc Institutein Palo Alto (USA), demonstrated that recombinases could be programmed to reverse, cut or insert personalized DNA sequences in specific regions of the genome of the E.coli, the model chosen to test the technique. Additionally, the researchers identified other RNA bridges in other transposable elements, suggesting that there are several enzymes that would be useful as gene editing tools.
Hsu explains that RNA bridges “offer the unique ability to simultaneously recognize and manipulate two DNA sequences for insertion, excision or inversion in a single step, opening up new possibilities that are not easily achievable with current CRISPR systems.” “CRISPR requires the repair of cellular DNA after making a cut, while “bridge editing” can perform DNA recombination without requiring cellular DNA repair mechanisms,” continues the researcher, from the University of California at Berkeley. . “This could potentially lead to safer gene editing results, because CRISPR cuts can cause large deletions or unwanted translocations at the cut site,” he concludes.
Lluís Montoliu, a researcher at the National Center for Biotechnology of the CSIC who has not participated in the study, agrees on the usefulness that the new technique can have to go beyond CRISPR and modify larger regions of the genome in a safer way, something that increases the therapeutic potential . “Hsu’s laboratory describes a new DNA genetic modification system that makes it possible to overcome the shortcomings of CRISPR-Cas systems, which are very useful for inactivating genes by mutation or for changing or inserting/deleting a few nucleotides (letters) in the genome but clearly ineffective. to support, at a clinical level, the insertion, deletion or inversion of large DNA sequences, which are usually present, as chromosomal alterations, in many diseases of genetic origin,” he indicates.
As limitations, Montoliu points out that the system is still “associated with modifications in other similar places in the genome and with a variable efficiency, between 5% and 99%, with a very wide range of response”, although he believes that “surely will improve with future optimization of the system.” Furthermore, he recalls that “the experiments are only reported in bacteria and we do not know if it will work in mammalian cells.”
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