Gene therapy

Great advances made in the last ten years mean that the use of gene therapy to treat and cure primary immunodeficiencies (PIDs) is a reality.

What is gene therapy?

Gene therapy is a ‘mini gene transplant’. Doctors remove stem cells from the patient with a PID, replace the defective genes inside the cells with new, healthy, fully functioning genes and then give the gene-corrected cells back to the patient. The cells can then go on to produce the cells or proteins needed to fight infection.

Having gene therapy is similar to having a bone marrow transplant. Patients may need chemotherapy beforehand to get rid of as many cells with the genetic defect as possible. This is called ‘conditioning’. In some forms of severe combined immunodeficiency, gene therapy can be undertaken with little or no conditioning. In most other forms of PID, chemotherapy that is similar to what is used for a bone marrow transplant is needed.

A big advantage of gene therapy is that it uses the patient’s own cells, so rejection is not a problem like it can be with bone marrow transplants, where the cells come from another person. Also, because it uses the patient’s own cells, gene therapy avoids graft-versus-host disease, which is one of the major problems associated with a bone marrow transplant.

Gene therapy is not without risk and can have serious side effects. It is still considered an experimental medicine for some conditions but for others, such as ADA-SCID, it is close to being the recommended route of treatment when a well-matched bone marrow donor cannot be found.

How does gene therapy work?

Scientists start by attaching the normal, healthy gene they want to give the patient to a harmless virus called a vector.

They remove genetic material from the vector and replace it with genetic instructions to make a healthy copy of the person’s missing or mutated gene.

They then mix the vector and new gene with bone marrow from the patient.

The vector carrying the normal gene will penetrate the stem cells in the patient’s bone marrow and replace the defective gene with the healthy gene.

Doctors then grow these corrected cells in an incubator. Once they have enough, they put them back into the patient. The bone marrow will gradually absorb them. The new cells can then start making healthy white blood cells able to fight infection.

Until now, gene therapy trials for many immunodeficiencies have used ‘retroviral’ vectors. However, scientists now believe ‘lentiviruses’ may be more effective, so future trials will use these.

How safe are vectors?

Scientists spend a long time researching what the safest and most effective vectors are to use for gene therapy. They always ‘inactivate’ the vector viruses, making them harmless.

They test vectors on ‘cell models’ and animals. They will check if the vector damages animals’ organs and whether it works on them. They will also work out how much of a particular vector is needed to make it effective.

Scientists may then do patient trials, as animal and lab tests cannot guarantee the safety of any treatment.

Scientists test and make vectors under stringent conditions in special laboratories to make sure what they produce is of the highest quality possible and will pass regulatory authority tests so the vectors can be used in patients.

What are the criteria for treating PIDs with gene therapy?

Because it is still in its experimental stage, regulatory authorities and doctors have to approve any gene therapy treatment. They will weigh up the risks and benefits for each person put forward for it. They will also explain these thoroughly to the patient, and must have the patient’s consent before treatment.

Using gene therapy to treat a PID is allowed only if:

  • no bone marrow match is available OR the patient is too ill to have a bone marrow transplant


  • the patient has a life-threatening infection unresponsive to conventional treatment, including steroids.

The UK regulatory authorities that govern the use of gene therapy for PIDs are:

Gene therapy clinical trials

The first clinical trials using gene therapy to treat PIDs began in the early 1990s.

Gene therapy trials so far have succeeded in saving and extending the lives of many people with life-threatening infections.

Here we give you an update on how many people with PIDs have been treated by gene therapy and the outcomes:

Some statistics:

  • X-linked severe combined immunodeficiency (X-SCID)

Over 25 children have had gene therapy for X-SCID. In the first two trials, which treated 20 boys, the majority recovered their immune systems but five developed a leukaemia. This was because the retroviruses used in those trials were able to turn on oncogenes. Doctors are now undertaking trials using newly designed vectors that have a decreased ability to turn on oncogenes. New trials with these vectors are also showing recovery of the immune system. It is too early to say if they are safer and we will have to wait for a few more years for that information.

  • X-linked chronic granulomatous disease (CGD)

Since 2000, 14 people with CGD (children and adults) have had gene therapy in centres in the US, Europe and Korea.
 Of these, nine had treatment in Europe – in Switzerland, Germany and the UK (Great Ormond Street Hospital). 
Gene therapy cleared infections in all of these patients. However, none were cured permanently. Eight/nine people who received gene therapy in Europe are still alive. Three of them have gone on to have a bone marrow transplant.

  • WiskottAldrich syndrome (WAS)

Trials of gene therapy for WAS using retroviral vectors in Germany showed that gene therapy could correct the disease but unfortunately, as seen in X-SCID, this was also associated with the development of leukaemia in 7 out of 10 boys treated. New trials using lentiviruses are underway and are showing encouraging results. Although these lentiviral vectors are safer in the laboratory, it is too early to say if these are safer in patients.

  • Adenosine deaminase deficiency (ADA)

Forty-two children with ADA-SCID have been treated in London, Milan and the US. All the trials used retroviral vectors and all children have survived. Twenty-nine of the children have been able to stop enzyme replacement, which means that their immune system has recovered because of gene therapy alone.

This is very promising and means that gene therapy for ADA-SCID could become a standard medicine. Because of the concerns of using retroviral vectors, new trials using lentiviral vectors have just started.

Trials of gene therapy for three other forms of SCID are expected to start in the next three years. There is also work in the laboratory to develop gene therapy for X-linked lymphoproliferative disorder (XLP) and two forms of hemophagocytic lymphohistiocytosis (HLH).

What have scientists learned from clinical trials so far?

Treatment can have serious side effects – the most important concern has been related to the development of leukaemias in three different diseases following gene therapy. This is related to the retroviral vectors used and their ability to turn on neighbouring genes, especially oncogenes. Newer vector designs (especially lentiviral vectors) appear to be safer in the laboratory and in tests on animals. The trials that are underway will show whether these have long-term safety in patients.

Sometimes the gene-corrected cells do not engraft in the marrow so it does not provide a permanent cure. Changing vectors and the chemotherapy process may improve how long the corrected cells last.

What is the future of gene therapy for PIDs?

The information so far from clinical trials has allowed scientists to significantly improve vectors to make treatment more effective and safer. Scientists have also developed new ways to help predict how well gene therapy will work and its safety before treating patients.

However, there are two key things scientists are concentrating on to improve success rates in the future:

Improving engraftment of corrected cells

Until now, scientists have used mild chemotherapy to knock out cells carrying the CGD genes before the patient receives the corrected cells. This is so the healthy cells have a better chance of establishing themselves (engrafting) in the bone marrow and out-competing the cells still carrying the genetic defect.

Scientists are looking into whether more intensive chemotherapy may help more cells engraft. Doctors would have to weigh up the benefits of this against the risks for each patient, particularly if someone has a serious infection.

Improving the safety and effectiveness of gene therapy

Switching from retroviral-based vectors to lentiviral vectors – which scientists are doing now – may make gene therapy safer and more effective.

The advantage of lentiviral vectors is that patients’ cells do not need to undergo so many manipulations in the laboratory. This means they are more likely to be able to engraft in the bone marrow.

Where are the centres of excellence in gene therapy?

In the UK, gene therapy for PIDs is only available at Great Ormond Street Hospital. There are a few other centres in Europe, including Hopital Necker in Paris, Children’s Hospital in Zurich and San Rafaelle Hospital in Milan.

How do the centres work together?

If a patient in the UK has a PID and is eligible for gene therapy, then the child can be referred to Great Ormond Street Hospital for treatment. The patient has to meet the entry requirements for the gene therapy trial or a case needs to be made for why the child should have gene therapy rather than a bone marrow transplant. EU healthcare agreements also mean that patients can be referred across Europe for treatment, if that treatment is not available in their own country. For that reason, patients with PID from across Europe have been referred to Great Ormond Street Hospital for treatment.