In gene therapy, genes are inserted into a human genome for the treatment of hereditary diseases. Gene therapy is generally used for distinct diseases, such as SCID or septic granulomatosis, that cannot be controlled by conventional therapeutic approaches.
What is gene therapy?
Gene therapy involves inserting genes into a human genome to treat inherited diseases. Gene therapy is the insertion of genes or genome segments into human cells. It aims at compensating a genetic defect for the treatment of hereditary diseases. In general, a distinction can be made between somatic gene therapy and germline therapy. In somatic gene therapy, body cells are modified in such a way that only the genetic material of the cells of the body tissue to be specifically treated is modified. Accordingly, the modified genetic information is not passed on to the next generation. In the context of germ line therapy, on the other hand, which is prohibited in almost all countries, a modification of the genetic information takes place in cells of the germ line. In addition, depending on the therapeutic strategy, a distinction is made between substitution therapy (replacement of defective genome segments), addition therapy (enhancement of specific gene functions such as immune defense in cancer or infectious diseases) and suppression therapy (inactivation of pathogenic gene activities). In addition, because the gene sequence can be inserted into the target cell permanently or for a limited time, the effect of gene therapy can be permanent or temporary.
Function, effect, and targets
In general, gene therapy aims to enable the target cell to synthesize substances essential to the organism (including proteins, enzymes) by replacing the defective gene with an intact one. The substitution of the genetic material can be carried out outside the body (ex vivo). For this purpose, the cells showing the defect to be treated are taken from the affected person and equipped with an intact gene. The modified cells are then reintroduced into the affected person. Gene transport into the cell can be ensured by various methods. In so-called chemical transfection, an electrical connection affects the cell membrane in such a way that the therapeutic gene can enter the cell interior. Physically, the modified genetic material can enter the cell interior by microinjection or an electrical pulse that causes temporary permeability of the cell membrane (electroporation). In addition, the modified information can be shot into the cell interior on small gold beads (particle gun). In the course of transfection by means of erythrocyte ghosts, erythrocytes (red blood cells) with the therapeutic genes are brought into lysis in a solution. This causes the cell membranes to open briefly and the gene sequence can enter. Subsequently, the modified erythrocytes are fused with the target cells. In addition, genetically modified viruses can be injected by a process known as transduction. Since viruses depend on a host’s metabolism to replicate, they can serve as so-called gene ferries by introducing the new, healthy genetic material into the target cells. DNA, RNA and especially retroviruses are used for the transduction process. Suitable target cells include liver cells, T cells (T lymphocytes), and bone marrow cells. Gene therapy is mainly used in severe immune system diseases such as SCID (defective T lymphocytes) or septic granulomatosis (defective neutrophil granulocytes). Furthermore, it represents a possible alternative therapy for tumors, serious infectious diseases such as HIV, hepatitis B and C, tuberculosis or malaria, whereby the therapeutic possibilities are still being clinically explored, especially with regard to HIV and tuberculosis. Gene therapy transduction with retroviruses on autologous hematopoietic stem cells is a particular possibility for beta-thallassemia (impaired beta-globin synthesis).
Risks, side effects, and hazards
While only a few diseases can be treated by gene therapy, the risks, on the other hand, cannot be fully assessed in many cases because of the therapy’s low stage of development.The greatest risk in gene therapy is the previously undirected integration of the therapeutic gene sequence into the target cell. If the integration into the genome of the target cell is incorrect, the function of intact gene sequences can be impaired and, if necessary, other serious diseases can be triggered. For example, protooncogenes adjacent to the inserted gene can be activated, which can impair normal cell growth and trigger cancer (insertional mutagenesis). Corresponding results were observed in a Paris study, among others. After initial success, it turned out that some children treated with gene therapy developed leukemia. In addition, the immune system can mark the modified target cells as foreign and attack them (immunogenicity). Finally, in the case of transduction with viruses, there is a risk that the person treated with gene therapy will become infected with a wild-type of the virus used as a ferry in his or her case and that this will mobilize the genetically modified sequence from the genome to such an extent (mobilization) that it can integrate at an undesired site with the corresponding consequences.