What is gene therapy?


Genes are the basic units of heredity. They contain the information to makes us in the first place and then to control the mechanisms of the body. Genes carry this information recorded in the form of DNA, which is made up of long sequences of four chemical compounds known by the letters A, C, G and T.

 Genes act by coding for proteins – the sequence of “letters” in each gene is translated to make a specific protein – and it is the interaction of these proteins that makes the body function.

 In genetic conditions like A-T, a particular gene carries a mutation, that is, a change to the DNA which results either in the gene being unable to produce a protein or in its producing a protein which is unable to carry out its function. In the case of A-T, the gene affected is the ATM gene, which is unable to produce properly functioning ATM protein.

 Gene therapy

Gene therapy aims to correct the functioning of a gene. There are a number of possible ways to attempt to do this but the most common approach, and the one we will focus on here, is to insert a normally-functioning gene or length of DNA into the genome in particular cells.

To do this requires two principal elements: a corrected gene or section of DNA and a carrier molecule to transport the gene to the correct cells within the patient. This carrier is called a ‘vector’.

A number of different types of vectors have been developed, but the most common are based on viruses. This is because viruses are very efficient at delivering genes into cells. Natural viruses deliver their own genes, which allow the virus to multiply (often killing the infected cell) and spread to other cells — this is what causes some diseases (such as colds, ‘flu, measles etc.). The viruses used for gene therapy are genetically altered, removing viral genes (so they can’t cause disease), and replacing them with the relevant human gene to be delivered into the target cells.

The idea is that once the new gene or genetic material has been delivered into the cell, its genetic code is read and the cell starts to produce the correct protein, and normal functioning is restored.


The concept sounds relatively simple, but in reality there are many difficulties to overcome. While there are experiments going on for a number of treatments and conditions, to date only one gene therapy treatment has been approved for use in Europe and none so far in the USA.

The problems to be overcome include:

  • Getting the gene to the right cells. The target is normally a very specific organ or set of cells. Clinical trials for treatment of some inherited blood disorders (especially immune deficiencies) are making good progress, because the blood stem cells (bone marrow cells that give rise to all blood cells) can be manipulated outside of the patient “in the petri dish”. This makes it much easier to introduce the genes, before the corrected cells are re-introduced into the body. Unfortunately, this is not an option for the brain!
  • Avoiding generating an immune response. The body’s immune system is designed to target and eliminate ‘foreign bodies’ and a virus or cell carrying ‘new’ DNA may well seem foreign and be attacked by the immune system.
  • Toxicity and side effects. Even the genetically altered viruses may still cause some toxicity or inflammation. They may also not be easy to control once inside the body
  • Length of effectiveness of treatment. Only certain types of vector allow the new gene to be passed on to daughter cells, when the original cell divides — and the ATM gene is too large for vectors that allow this. For other types of vector, the effects of gene therapy may be short lived, as the new gene will not be passed on when cells divide. Of course the effect is also lost if the treated cells die. Even when cells are long-lasting, as in the brain, we need to be sure that the new gene will be equally stable over time.

Gene therapy and A-T

There are a number of specific issues facing gene therapy for A-T which make it a much more difficult target than many other inherited disorders. One obvious one is that A-T is a complex condition affecting many different processes in the body. You need to decide which cells to target.

Most people would consider the cerebellum to be the most logical target, since neurological disability is the element which has the most major impact on life for people with A-T and in addition the problems it causes with swallowing and clearing the lungs are likely to play a major part in the incidence of lung disease. However, the brain is a very sensitive and well protected organ which makes it very difficult to target. It also seems very likely that it is not just the cerebellum that is affected by A-T, but also other areas of the brain.

Other challenges include:

  • The size of the gene: ATM is a very big gene and produces a very big protein. This means that there is a lot of DNA to be carried and many potential vectors (including those that provide the most stable persistence) just do not have the capacity to carry this load.
  • Getting to the cerebellum. The easiest way to get substances into the body is through the blood. However, to get from the blood to the brain, you have to pass through a membrane called the ‘blood-brain barrier’. This will only allow very small molecules to pass through it, and as we have seen, ATM is not a small molecule. Other approaches, such as direct injection are also particularly complicated when trying to get to the brain. The encouraging progress with inherited blood diseases has been possible because the gene transfer can be done “in the petri dish”, before the blood precursor cells are returned to the patient (and the genes involved are much smaller).
  • Also, it is not clear what proportion of cells would have to be treated in the cerebellum in order to be beneficial. However it seems likely that a much greater efficiency would be required than for disorders such as LPL deficiency or the immune deficiencies.
  • The fact that we are dealing with the brain means that any immediate or long term side effects could potentially be catastrophic.
  • The fact that A-T causes a reduced ability to deal with DNA damage and an increased susceptibility to cancer means that people with the condition are potentially much more vulnerable to potentially harmful consequences of gene therapy.

Nevertheless, while all these issues are serious, progress is being made in overcoming many of the problems facing gene therapy. Although as we have seen, A-T appears a more challenging target than many other disorders, it is likely that in the medium to long term this could be one of the most likely bases for an effective treatment for A-T.

(With sincere thanks to Dr Peter Searle and Prof Malcolm Taylor of the University of Birmingham for their input to this article)




Diagram of DNA showing bases

DNA has a characteristic double-helix form.





Gene therapy

In gene therapy, a corrected length of DN is inserted into the gene.