Molecular knowledge of the basis of heredity - genes and their regulatory elements - naturally led to the idea of modifying the cellular genome for therapeutic purposes: firstly, to correct an inherited disease attributable to the mutation of a gene by bringing a functional copy of the gene into the cells. This idea emerged in the 1970s, when it became possible to use modified viruses as vectors for the genetic sequence of therapeutic interest. Today, gene therapy can also be conceived as a means of inhibiting the expression of a deleterious mutated gene, modifying the expression of a mutated gene, adding a new gene to create a new function, or even directly correcting a mutation.
In addition to the gene of interest, making gene therapy effective involves providing a promoter sequence that regulates expression of the therapeutic gene, and using a vector. The challenges are complex, which explains the slow development of this approach: targeting the relevant cell, obtaining an adequate level of expression (neither too much nor too little) of the gene of interest, avoiding a toxic effect and an immune reaction against the vector and/or the transgene. Two strategies are generally used: on the one hand, vectors that enable the gene of interest to be integrated into the cell genome and thus replicated at each cell division, and on the other, vectors that allow the gene of interest to persist without integration, thus avoiding any risk of genotoxicity. The latter vectors can only be used to target cells that divide little or not at all. The first category of vectors is represented by retroviruses, whose RNA, after reverse transcription into DNA, integrates into the cellular genome. The second category is essentially represented by adeno-associated viruses (AAV), which penetrate all cells and whose genetic material can persist in the episome state.
