The genetic editing makes it possible to rewrite a person's genome 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 shape. This deformity prevents them from circulating properly through the blood vessels, causing severe pain and premature death. In December 2023, the US approved the first treatment for this hereditary disease 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 a gene that works correctly.
This technology already has applications from hereditary genetic diseases to cancer immunotherapy, but poses some precision issues, such as cutting unwanted sequences, similar to the target to be eliminated, or releasing cut pieces of DNA that trigger an immune response that is harmful is for the patient. or genomic instability. This Wednesday the magazine Nature to publish two articles describing a new genetic editing mechanism, potentially more precise and with the ability to introduce long DNA sequences at specific locations in the genome.
Researchers have taken advantage of the ability of what is known as jumping genes (or transposable genetic elements), mobile elements that can move to different parts of the cell's genome or even to other microorganisms and play an essential role in the evolution and adaptation of living things. For their jumps through the genome, these elements use enzymes, recombinases, that build an RNA bridge between the DNA of origin and that of the place where it will 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 are used to choose the specific location where the desired piece of DNA is located. This versatility would make it possible, for example, to carry a functional copy of a gene to replace a defective copy that causes a disease, as in the case of sickle cell anemia. In one work, the authors managed to transfer a gene to a region of the bacterium'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 can be programmed to invert, cut or insert personalized DNA sequences into specific regions of the human genome. E.colithe model chosen to test the technique. In addition, 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 “provide the unique ability to simultaneously recognize and manipulate two DNA sequences for insertion, excision or inversion in a single step, opening up new possibilities not easily achievable with conventional sequences.” current CRISPR systems”. “CRISPR requires the repair of cellular DNA after making a cut, while bridge editing can perform DNA recombination without the need for cellular DNA repair mechanisms,” continues the researcher from the University of California, Berkeley. “This could potentially lead to safer gene editing results, as CRISPR cuts can cause large deletions or unwanted translocations at the cut site,” he concludes.
Lluis Montoliu, a researcher at CSIC's National Center for Biotechnology who did not participate in the study, agrees that the new technique can go beyond CRISPR and modify larger parts of the genome more safely, something that the chance increases therapeutic potential. “Hsu's laboratory describes a new DNA genetic modification system that allows to overcome the shortcomings of CRISPR-Cas systems, which are very useful for inactivating genes by mutation or for changing or inserting/deleting single nucleotides ( letters) in the genome, but clearly ineffective to support at the clinical level the insertion, deletion or inversion of large DNA sequences, which are usually present, as chromosomal changes, in many diseases of genetic origin,” he indicates.
As limitations, Montoliu points out that the system is still “associated with modifications at other similar sites in the genome and with variable efficiency, between 5% and 99%, with a very wide response range”, although he believes that “will certainly improve with future optimization of the system.” Also remember that “the experiments are only reported in bacteria and we don't know if it will work in mammalian cells.”
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