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Gene therapy: what is it?

We often hear about gene therapy, more and more often, but what exactly are we talking about? We are going to try to make this science that may seem complicated a little more understandable.

Do not hesitate to ask us your questions!

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Gene therapy is mainly for genetic diseases :

Genetic diseases are caused by mutations in a gene that are passed on from one generation to the next, or by mutations acquired during life that can lead to the development of cancer.

Genes carry information and are well protected at the heart of the cell, in the nucleus (fig1).

figure 1 From gene to DNA and chromosome in the cell structure.(Istock/ ttsz)

Moreover, the information is the same in all cells, but not all cells use it in the same way or at the same time. As a result, gene therapy approaches are unlike any other kind of therapeutic approach: they involve correcting information in the hope that the correction will improve a function.

The three main areas in which clinical trials are being conducted are single gene diseases, cancer and certain degenerative diseases such as Parkinson's disease or heart failure.

Principles of gene therapy

Because of this knowledge of genetics and the genes responsible for certain diseases, researchers have imagined correcting "sick" or dysfunctional genes directly. This is the reason for genetic engineering and gene therapy.

The development of gene therapy is based on two main principles:

- The introduction of genes ensuring lost or missing functions. This is the case with hemophilia A, due to the absence of a coagulation factor as a result of loss of gene function: gene therapy provides the gene for factor VIII and allows the blood to coagulate "normally".

- Blocking genes that produce unintended effects. One example is the use of small antisense RNAs.

To do this, two strategies have been developed (fig 2) :

  • Ex vivo therapy : This approach is the most successful because it is the simplest to implement. It consists of taking cells from the patient, modifying their genetic heritage in culture, and then self-grafting them so that they colonize the diseased organ or tissue. This strategy is successfully used to treat blood diseases (hemophilia, sickle cell disease, thalassemia, etc.). Indeed, blood is a rapidly renewing tissue entirely derived from stem cells located in the bone marrow: a marrow transplant allows the blood tissue to be entirely renewed from the modified stem cells.

  • In vivo therapy : In this case, it is not possible to replace the entire tissue, and the cells are treated at the heart of the organism by providing them with the therapeutic gene. This strategy is currently limited by the extent of the areas to be treated, as we do not yet know how to reach all the cells in the body.

Fig 2 : The two strategies of gene therapy(« in La Génétique pour les Nuls, Dr Patrice Bourgeois, Dr Tara Rodden, illustration de Fabrice Del Rio Ruiz © Éditions First, 2021 )

Focus on the RNA approach

In this approach, the aim is to try to block the action of the defective gene at the heart of the cells. This is not really gene therapy, but rather genetically targeted therapy, without modifying the DNA. To do this, we try, for example, to destroy an intermediate produced by the gene in question, using approaches called "antisense RNA". In hereditary amyloidosis, for example, an abnormal protein is produced because of a mutation in a gene. By injecting an antisense RNA capable of destroying the abnormal message, patients have had significant improvement in their neurological symptoms. They still have the mutation in their DNA, but the effect of the mutation is prevented.

Also in this category is exon-skipping therapy, which will be the subject of a future post.

Gene therapy itself

To bring a normal copy of the gene into the cells to restore the action of the defective gene, a vector - usually an inactivated virus - must be used. Another more recent approach is to correct the defect directly on the defective gene so that it becomes normal again, this is the CRISPR-Cas9 technology (which was the subject of a Nobel Prize)

Of these gene therapy approaches, only the one using vectors has resulted in authorized drugs for the moment. An example of a vector authorized for sale since the end of 2017 in the USA is Luxturna: it treats retinal dystrophy linked to mutations in the RPE65 gene.

High hopes despite some challenges.

At this time, it is not known how to target the entire body. The duration of treatment is also unknown. The cost of all these approaches is high, and large-scale industrial production of vectors is not yet sufficient. The long-term reactions of the body to inactivated viruses are not yet fully understood, but it is likely that they trigger an immune response. Finally, to date, it is only possible to treat diseases caused by mutations in a single gene at a time (monogenic diseases).

Many trials are underway as shown in the following iconography

Patrice Bourgeois

Chief engineer in genetics at the Timone University Hospital in Marseille, where he is involved in the diagnosis of rare diseases. He teaches biology, genetics and embryology in the Marseille area. He is the co-author of La Bioéthique pour les Nuls en 50 notions clés (First).

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