Using genes as medicine: this is the idea behind gene therapy. Therapeutic strategy consisting in modifying genes to cure a disease, gene therapy is still in its infancy but its first results are promising.

Definition of gene therapy

Gene therapy involves genetically modifying cells to prevent or cure disease. It is based on the transfer of a therapeutic gene or a copy of a functional gene into specific cells, with the aim of repairing a genetic defect.

The main principles of gene therapy

Each human being is made up of some 70 billion cells. Each cell contains 000 pairs of chromosomes, made up of a double helix-shaped filament, DNA (deoxyribonucleic acid). DNA is divided into a few thousand portions, genes, of which we carry around 23 copies. These genes make up the genome, a unique genetic heritage transmitted by both parents, which contains all the information necessary for the development and functioning of the body. The genes indeed indicate to each cell its role in the organism.

This information is delivered thanks to a code, a unique combination of the 4 nitrogenous bases (adenine, thymine, cytosine and guanine) which make up DNA. With code, DNA makes RNA, the messenger that contains all the information needed (called exons) to produce proteins, each of which will play a specific role in the body. We thus produce tens of thousands of proteins essential for the functioning of our body.

A modification in the sequence of a gene therefore alters the production of the protein, which can no longer play its role correctly. Depending on the gene concerned, this can therefore lead to a wide variety of diseases: cancers, myopathies, cystic fibrosis, etc.

The principle of therapy is therefore to provide, thanks to a therapeutic gene, a correct code so that the cells can produce the protein lacking. This gene approach first involves knowing precisely the mechanisms of the disease, the gene involved and the role of the protein for which it codes.

Gene therapy research focuses on many diseases:

• cancers (65% of current research) 
• monogenic diseases, i.e. diseases which affect only one gene (hemophilia B, thalassemia) 
• infectious diseases (HIV) 
• cardiovascular disease 
• neurodegenerative diseases (Parkinson’s disease, Alzheimer’s disease, adrenoleukodystrophy, Sanfilippo disease)
• dermatological diseases (junctional epidermolysis bullosa, dystrophic epidermolysis bullosa)
• eye diseases (glaucoma) 
• etc.

Most of the trials are still in phase I or II research, but some have already resulted in the marketing of drugs. These include:

• Imlygic, the first oncolytic immunotherapy against melanoma, which received its Marketing Authorization (Marketing Authorization) in 2015. It uses a genetically modified herpes simplex-1 virus to infect cancer cells.
• Strimvelis, the first therapy based on stem cells, obtained its Marketing Authorization in 2016. It is intended for children suffering from alymphocytosis, a rare genetic immune disease (“bubble baby” syndrome)
• the drug Yescarta is indicated for the treatment of two types of aggressive non-Hodgkin lymphoma: diffuse large B-cell lymphoma (LDGCB) and refractory or relapsed primary mediastinal large B-cell lymphoma (LMPGCB). It received its Marketing Authorization in 2018.

Different approaches exist in gene therapy:

• the replacement of a diseased gene, by importing the copy of a functional gene or “therapeutic gene” into a target cell. This can be done either in vivo: the therapeutic gene is injected directly into the patient’s body. Or in vitro: stem cells are taken from the spinal cord, modified in the laboratory and then reinjected into the patient.
• genomic editing consists of directly repairing a genetic mutation in the cell. Enzymes, called nucleases, will cut the gene at the site of its mutation, then a segment of DNA then makes it possible to repair the altered gene. However, this approach is still only experimental.
• modifying RNA, so that the cell produces a functional protein.
• the use of modified viruses, called oncolytics, to kill cancer cells.

To get the therapeutic gene into the patient’s cells, gene therapy uses so-called vectors. They are often viral vectors, the toxic potential of which has been canceled. Researchers are currently working on the development of non-viral vectors.

It was in the 1950s, thanks to a better knowledge of the human genome, that the concept of gene therapy was born. However, it took several decades to obtain the first results, which we owe to French researchers. In 1999, Alain Fischer and his team at Inserm managed to treat “baby bubbles” suffering from a severe combined immunodeficiency linked to the X chromosome (DICS-X). The team has indeed succeeded in inserting a normal copy of the altered gene into the body of sick children, using a retrovirus-type viral vector.