GENETIC SELECTION > INFORMATION > SHEET 6

GENE THERAPY

Until the advent of gene therapy, it was only possible to suppress the symptoms of inherited disease. Only a small proportion of those affected were able to lead fully active lives. Gene therapy is the attempted repair or replacement of disease-causing genes by the introduction of functional genes. In this way doctors hope to treat many inherited diseases effectively for the first time. The startling rapidity with which gene therapy has developed stems from two factors:

a much improved understanding of the molecular basis of many diseases,
the development of techniques to isolate selected genes of interest and to study and change them outside the body.

Unlike conventional treatments, which attempt to deal with the consequences of a defect, gene therapy aims to correct the defective gene itself.

Gene therapy introduces new genes into the body cells. Two quite separate types of gene therapy can be envisaged:

Germ-line therapy - where the modifications affect the inherited genetic material of sex cells and are passed onto
future generations.

Somatic gene therapy - where genes are introduced to ordinary body cells. However, in this case, the sex cells are not altered in any way and the genetic modification cannot be passed onto future generations.

GENE THERAPY TRIALS BEGIN

Gene therapy trials have been given the go-ahead by medical authorities in many countries. Although this work is still in its infancy, the early results of some trials are encouraging.

The modern era of gene therapy began in the USA, in 1990, with the extremely rare but incurable immunodeficiency, ADA (adenosine deaminase) deficiency. Patients with ADA deficiency do not develop an immune system, so cannot fight
infections; they need constant protection from pathogens. Two children were given a working copy of the ADA gene, which was inserted into some of their white blood cells.

Five years on, these children are living comparatively normal lives. This example shows that new genes can be introduced into human cells, replacing missing function.

Nevertheless, because the modified cells eventually die, the treatment has to be repeated at regular intervals. Manipulation of stem cells could overcome this problem, since unlike most body cells, they continue to divide throughout life. By replacing old, worn out cells in the bone marrow, for example, they constantly replenish the body’s circulating blood cells. If these cells could be corrected by gene therapy, they would provide a life-long supply of the correct protein.

ADA deficiency is extremely rare - only about a dozen people have been treated this way. But more than 200 trials of different gene therapy have been approved in recent years. Most are cancer trials, though gene therapies for cystic fibrosis and heart diseases have also been attempted. So far the results have not been very positive but it is still early days.

APPLICATIONS OF GENE THERAPY

Gene therapy covers a range of techniques and is potentially applicable both to:

single gene disorders - caused by a single absent or malfunctioning gene,
multifactorial diseases - where environmental factors as well as genes contribute to susceptibility.

1.Treatment of single gene disorders

In 1993, researchers at Oxford and Cambridge in the UK announced that they had restored normal function to cells in the lungs of mice with artificially-induced cystic fibrosis. They did so by squirting into the lungs, copies of the cystic fibrosis
gene encased in liposomes (tiny globules of fat). The liposomes fused with the animal’s cell membranes, allowing the DNA to pass through into the cells and thus correct the defect. Trials with humans began shortly after, and some success in dealing with the symptoms of cystic fibrosis has been reported, although this therapy is not a cure.

2.Treatment of multifactorial diseases

(a) Coronary heart disease

The therapeutic gene attempts to counterbalance the effects of the other inherited and environmental factors. For example, expression of the gene for the LDL (low-density lipoprotein) receptor in the liver would increase the organ’s LDL uptake from the blood. Since LDL particles in the blood are mostly cholesterol, blood cholesterol levels would be lowered, reducing the risk of heart attacks.

(b) Cancer therapies

Cancer develops when cells proliferate out of control. The object of gene therapy with cancer patients is to rid the body of the tumour cells without damaging normal body tissues. French Anderson and colleagues at the National Cancer
Institute and National Heart, Lung and Blood Institute in Bethesda, USA, are currently pioneering a therapy along these lines. The aim is to optimise the treatment of cancer by using the patients’ own white blood cells. White blood cells were taken from patients and treated with interleukin-2, a natural substance, which stimulates their growth and cancer killing abilities. A gene was introduced into the chromosomes of the treated white blood cells before returning them back to the patients. This newly introduced gene allows doctors to monitor the success of the interleukin-2 treatment.

ETHICAL ISSUES

There is general agreement that gene therapy should, for the time being, be restricted to somatic therapy - where genes are introduced into ordinary body cells, and its use should be limited to life threatening conditions for which there is no alternative treatment. The ethical issues are reasonably straightforward for this form of gene therapy, as any individual being offered it can decide whether or not to accept treatment. Replacing damaged DNA is not much different from replacing a damaged kidney and the same choices must be made by the person who receives it (or by their parents).

Changing genes in sex cells alters the inheritance of someone who has no choice as, in a few years, the manipulated gene will be carried not just by those who agreed to it but by their descendents. On this and other grounds germ-line therapy is currently generally thought to be unacceptable. All the national studies of the ethics of gene therapy have rejected, at least for the time being, the idea of germ-line therapy. In France and Germany, the recommendation was for outright prohibition. In Sweden, the conclusion was that any proposals for germ-line therapy would have to come under severe ethical examination. In Britain, the Clothier Committee in 1992 ruled out germ-line therapy on the grounds that:

There is at present insufficent knowledge to evaluate the risks to future generations.
Ethical issues in gene therapy
Clothier Committee

The question is, will germ-line therapy always be thought of as being ethically unsound?

In the case of serious genetic disease, there are some people who believe germ-line therapy would be justified:

If it became possible, as indeed it might, to eradicate for ever immune deficiency disease, in particular AIDS, through germ-line therapy, the present or immediate advantage might seem sufficiently great to outweigh the argument from ignorance (however keenly felt). I would not like to rule out for ever the legitimacy of genetic manipulation at the embryonic stage.
Baroness Mary Warnock
Science and Public Affairs 1992

It is foolish and ethically unacceptable to use germ-line therapy to make changes in people’s DNA that can be inherited and it should be outlawed.
Chairwoman of the group of Advisers on Ethical Implications of Biotechnology of the EC
New Statesman Dec 23/31 1994, p11