Gene therapy: what you should know

The concept of replacing defective genes with healthy ones spurred high hopes in the early nineties. Since the first gene therapy trial in 1990, though, several setbacks have somewhat dampened the early optimism.

The potential for treating conditions like Parkinson's disease, cystic fibrosis, and cancer, just to name a few, does, however, remain substantial, and researchers are hard at work looking for ways around the various difficulties.

What is gene therapy?

The basic function of genes is to regulate the production of proteins required for the healthy working of cells. Thus, genetic defects manifest in either too little or too much of a protein being produced.

The aim of gene therapy is to replace the defective gene with a healthy one. The correct proteins will then be produced, and the disease will be cured.

In an ideal scenario, the cell with the corrected DNA will multiply, producing more copies of the corrected gene, thus freeing the body of the genetic abnormality and curing the disease.

However, successfully transferring healthy genes into affected cells, and getting it to repair the abnormalities, is a very tricky process, and has met with little success. Much of the current research revolves around developing safe and reliable delivery mechanisms.

En vivo and Ex vivo therapies

In en vivo gene therapy cells are removed from a patient's body, genetically modified, and placed back into the patient's body. This technique is particularly useful in treating blood diseases, where blood can be removed and returned relatively easily.

In most diseases, however, cells cannot simply be extracted and returned. Thus, for genetic heart conditions, for example, en vivo therapies are required where the changes take place inside the patient's body.

To do this, genetic information is sent to the affected cells inside a vector (a kind of transport mechanism). In most cases, researchers are using non-threatening viruses to fulfil this transport function.

Viruses sneak past body's defences

Viruses have evolved to be very good at sneaking past the body's defences, infecting cells, and getting those cells to multiply the virus. For the purposes of gene therapy, viruses from the retrovirus and adenovirus classes seem to be most efficient at this task.

Retroviruses carry genetic information in the form of RNA (a molecule similar to DNA that helps interpret the information stored in DNA). Once inside the target cell, a DNA copy is made of the RNA, by means of a process called reverse transcription. Once the new DNA is incorporated into the cell, new copies of the cell will all contain the modified genes.

Adenoviruses carry genetic information in the form of DNA. Even though they deliver the DNA into the nucleus of the target cell, the DNA is not incorporated. Thus, even though the new DNA will be transcribed, it will not be carried over to descendents of the cell.

As a result, treatment with adenoviruses would be ongoing, as opposed to retroviruses, which, under ideal circumstances, may only require a once-off treatment.

A third option is the use of adeno-associated viruses (AAV). These viruses contain a comparatively small amount of genetic information and are harder to produce than the retroviruses and adenoviruses. They do however have the advantage that they tend not to elicit an immune response.

Difficulties with viruses

A lack of control as to exactly how and where genes are integrated into target cells can be very dangerous. This could lead to an unwanted expression of the gene, and could in some cases make the cell cancerous. This is particularly problematic when working with retroviruses.

A second problem is that the ideal of a single application of therapy, correcting genetic defects once and for all, is far from being realised. Most genetic therapies need to be repeated from time to time.

Thirdly, the use of viruses to deliver genetic information runs the risk of eliciting an immune response. This could be particularly problematic with repeated applications of a therapy as the body becomes more adept at fighting the virus.

The future of gene therapy

In a small number of cases gene therapy has successfully been used to treat X-linked severe combined immunodeficiency, (X-SCID). The treatment is however quite risky, with some patients having developed leukaemia-like symptoms.

Apart from this gene therapy has had very little success in humans. There has, however, been positive results from trials using gene therapies to treat animals suffering from arthritis, brain cancer, sickle cell anaemia, and retinoschisis, among others.

Researchers are exploring a number of avenues in search of effective gene therapies including experiments with a number of non-viral delivery methods. Of these, attempts to introduce an artificial 47th chromosome into target cells, is of the most interesting.

Recent advances include the recognition of RNA interference, or gene silencing, as a possible avenue for the treatment of Huntington's disease, and the discovery of a way to deliver genetic information into the brain, something which viral vectors are too large to do. - (Marcus Low, Health24, October 2005)

Source: Human genome project

Visit the Human Genome Project for more information.

October 2005

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