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Wednesday, 23 October 2019

New, high-precision method of genetic editing helps to neutralize most genetic diseases


In recent years, genetic publishing has grown considerably thanks to the development of the CRISPR-Cas9 genetic tool. If the latter has been revolutionary in the in situ modification of the genetic code, many biologists have pointed out its inaccuracy, which may result in the introduction of unintentional genetic errors. Recently, a team of American biochemists has developed a new gene editing technique that is both more efficient and accurate than CRISPR-Cas9. This method can thus edit the genome base by base, in order to cure a large number of genetic diseases.

US biologists have developed a powerful new genome editing system that could offer much better accuracy and efficiency than the current CRISPR standard technique. Although CRISPR-Cas9 is a breakthrough medical technology that has laid the foundation for modern genetic editing, including variants associated with a disease, its risk of vagueness has long been a concern.

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Specifically, researchers fear that the CRISPR-Cas9 edition has the risk of introducing errors in the form of uncontrolled insertions and deletions into the genetic code, called indel.

Researchers say this new system, described in the journal Nature and nicknamed "the main edition" by its inventors Broad Institute (MIT) and Harvard University, could change the game with a new protein that allows modification high precision genetic targets.

" One of the main aspirations in the biomolecular sciences is the ability to make precise changes to the genome, wherever they are, " says Broad Institute geneticist David Liu . " We do not know of any other mammalian cell editing technology that offers this level of versatility and accuracy, with so few byproducts ."


Reverse transcriptase and Cas9: a more accurate and versatile genetic edition

The basis of the new main editing method is an enzyme called reverse transcriptase. The CRISPR system also uses a Cas9 enzyme to cut DNA strands, so that other genetic sequences can be inserted. A breakthrough in 2017 by Liu's lab has dramatically improved system accuracy, allowing single-letter modifications of DNA base pairs, instead of replacing entire portions of code at a time.

The new method of genetic editing uses a combination of reverse transcriptase, Cas9 and a guide RNA (pegRNA) to precisely modify the targeted genetic sequences. Credits: Andrew V. Anzalone et al. 2019

Now, thanks to reverse transcriptase, used in conjunction with Cas9, genomic editing has been improved. In this system, a guide RNA called pegRNA guides a modified form of the Cas9 enzyme to cut only a single strand of DNA (preventing double-strand breaks that can induce unintentional perturbations). After that, reverse transcriptase directly copies the modified genetic information contained in the pegRNA to the targeted genomic site.

The versatility of the main edition quickly became evident when we developed this technology, " says biochemist Andrew Anzalone. " The fact that we can directly copy new genetic information into a target site has been a revelation. We were really excited.


Edit the basic genome by base to cure genetic diseases

The flexibility of the system means that for the first time, researchers can efficiently exchange one "letter" of DNA for another - among the following: adenine (A), cytosine (C), guanine (G) and thymine (T ) - 12 possible combinations. This is a clear improvement over what the Basic Editor achieved in 2017 has made possible: entirely new types of genetic modification of human diseases are now possible compared to what could be done before .

" With the main release, we can now directly correct the mutation of sickle cell disease and remove the four additional DNA bases that cause Tay Sachs disease, without completely cutting the DNA or needing DNA templates ", Liu explains.

Basic-based, highly accurate genetic editing can cure most pathological genetic dysfunctions. Credits: Nature

The team describes in detail these procedures in laboratory tests, among more than 175 modifications performed in human and mouse cells, with results producing fewer undesirable by-products and introducing fewer non-targeted changes than the Cas9 approach traditional. This is an important step, but given the fast pace at which these technologies are evolving, the researchers point out that the method is only at the beginning of its possibilities.

Exponential biomedical opportunities

" A great deal of additional research is needed to better understand and improve primary editing in a wide range of cell types and organisms, to evaluate the non-targeted major genome-wide editing, and to better characterize to what extent the main editions can affect the cells "write the authors.

Nevertheless, it is clear that there could be a huge opportunity for scaling up the theoretical and practical scale of genome editing - extending the technique, in principle, to 89% of known human pathogenic genetic variants, say the researchers.

Business opportunities are also potentially huge. Researchers will give other scientists a non-commercial license to explore this approach, but commercial applications of the patent-pending system may be more than significant for its inventors.


We are only at the beginning, but the first results seem fantastic. You will see many people using this new technique, "concludes Brittany Adamson, a geneticist at Princeton University.

This infographic summarizes the operation of the new editing method:


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