3 Somatic gene therapy
There is a distinction between somatic cells, those making up almost all of the body, and germline cells, which are the eggs and sperm and the cells that produce them. Somatic gene therapy is the transfer of genes into the somatic cells of the patient, such as cells of the bone marrow, and hence the new DNA does not enter the eggs or sperm. The genes transferred are usually normal alleles that could ‘correct’ the mutant or disease alleles of the recipient (see Study Note 2: The technique of somatic gene therapy).
Study Note 2: The technique of somatic gene therapy
The technique of somatic gene therapy involves inserting a normal gene into the appropriate cells of an individual affected with a genetic disease, thereby permanently correcting the disorder. Figure 2 outlines the simplest methods of getting genes into the person's cells using either viruses (which carry the human gene, in place of one of their own genes, into a cell) or liposomes (small fat-like molecules which can carry DNA into a cell). In some cells, the gene or genes become inserted into a chromosome in the nucleus.
The target cells might be bone marrow cells, which are easily isolated and re-implanted. Bone marrow cells continue to divide for a person's whole life to produce blood cells, so this approach is useful only if the gene you want to deliver has a biological role in the blood. Delivery of a gene that has a biological role in, say, the lungs, muscle, or liver would have to occur within those target organs. In many cases, accessing the appropriate tissue or, if the gene is required in multiple tissues (e.g. muscles throughout the body) ensuring it can be delivered where it is needed, is a major problem.
Will somatic gene therapy prevent the treated person from passing on the defective gene to their children?
No, because the gene they receive in somatic gene therapy does not enter their gametes.
However, there are three major scientific hurdles that have to be overcome before somatic gene therapy is likely to work. The first is getting the human gene into the patient's cells (using viruses or liposomes, Study Note 2). Adverse results in a UK/French gene therapy trial in 2002, including the death of one patient, highlighted some of the risks of using viruses. Following a safety review, the trial resumed because of the severity of the disease, and by the end of 2004, 17 out of 18 patients treated had experienced some improvements in their condition, with four experiencing significant improvements. Unfortunately, in early 2005 the trial had to stop again when a patient suffered an adverse reaction. Clearly, there is still some way to go with respect to safety of the techniques.
The second obstacle is getting the gene into the right cells. For example, for sickle cell disease (caused by defective haemoglobin in red blood cells), the cells to choose would be the patient's bone marrow cells. For cystic fibrosis, application in the lungs and gut would be needed. The lungs might be accessible via an aerosol spray. Treating the gut would need some way to deliver genes in a package that the patient would swallow, and which would protect them from digestive enzymes until they could act.
The final obstacle is making sure the gene is active, that is, switched on in the cell to produce the protein that the patient needs. This means it must be under the control of the sequence of DNA that is responsible for switching the gene on. The results do not have to be perfect to produce benefits. In cystic fibrosis, animal tests have shown that if the normal gene can be transferred to only five per cent of cells in the lungs, this restores some normal function.
The prospects for somatic therapy for single-gene diseases are still improving.
Why is gene therapy an unrealistic option for multifactorial diseases?
Because a number of genes are involved, multiple gene therapy would be required.
In general, current efforts to treat disease by somatic gene therapy do not pose any novel ethical issues, provided there is proper enforcement of informed consent in trials. There is concern, however, about where the successful development of techniques for germline gene therapy might lead.