New gene therapy trial for X-CGD

New gene therapy trial for X-CGD

CGD can be cured by bone marrow transplantation. However, this is sometimes associated with significant risk, in part because of toxicity associated with the treatment required to suppress the patient’s own bone marrow and allow the donor marrow to establish and grow. This is particularly true if the patient is very unwell at the time of transplant. There may also be toxicity because donor cells can recognise the host as foreign, and can therefore attack and destroy many body tissues. This is called graft versus host disease. To reduce this problem, and to make sure that the new marrow is not itself rejected, the bone marrow from the patient and from the donor are matched in a similar way to that of blood group matching for transfusion using HLA tissue typing. For patients with CGD, most experts would not recommend a bone marrow transplant unless the match was very good, either from a brother or sister, or from another unrelated donor. However, for a significant number of patients, there is no ideal matching donor.

For these reasons, GENETHON is testing strategies based on the use of harmless viruses, called lentiviruses, to correct the problem in phagocytic cells, and to provide a lifelong source of corrected cells by introducing the new gene into bone marrow. This is known as gene therapy. These viruses have been specially engineered in the laboratory in such a way that they are harmless, and unable to grow and infect other people. They are therefore simple carriers of the new gene into cells. Once in the cell the new gene is ‘spliced’ into the existing chromosomes, which carry all our genes. If this new gene can be placed in a special cell called a stem cell, which is normally present in the bone marrow and is like a ‘parent’ cell, then it will be passed onto all other cells in the blood, or ‘daughter cells’, including most importantly, the phagocytic cells.

Q. There have been other gene therapy trials for X-CGD. What’s new about this one?

This study is the first study conducted with this type of virus called lentivirus used to carry the new gene to the patient’s stem cells.

This new virus vector (lentivirus) has been specifically designed to avoid the potential risks and side effects linked to the previous virus vector such as affecting the function of another gene and causing a type of leukaemia.

The design and preliminary testing of this new virus vector was partly funded through the CGD Society.

Q. What does the trial want to achieve?

The purpose of this study is to determine whether enough stem cells can be given carrying the new gene to produce working phagocytic cells in the blood. It will also determine whether this helps to protect against infection, and for how long they will last. Finally it will help us know that the procedure is safe.

Q. What type of trial is it?

This is the first study conducted using this gene therapy virus in patients affected by X-CGD. All the patients enrolled in the study will receive the gene therapy and the study will take part in three different hospitals in three different countries (UK, Switzerland and Germany).

Q. Can all patients with X-CGD take part?

No. Not all X-CGD patients can be enrolled in the study. Patients that can take part have to fit certain criteria. They should be more than 23 months old and unable to benefit from a HLA identical family or unrelated or cord blood donor and not present with a co-infection with either HIV and/or hepatitis B and C. The physician in charge will check a patient’s eligibility to enter the clinical study on a case-by-case basis and discuss the procedure and its risks and benefits so that the patient can give informed consent.

Q. What is involved if someone decides to take part?

Six to twelve weeks before the gene therapy, some of the patient’s bone marrow cells will be collected in the centre. These cells will be frozen and stored for future use in the extremely unlikely event that bone marrow does not recover after treatment. This can be done in two ways. One way to do this is to place a needle into the hip bones under an anaesthetic procedure. This will take about an hour. When the patient wakes up the site will feel a bit bruised, but simple painkillers will take the pain away. The other way to collect some bone marrow cells is to give some small injections of chemicals into the skin for 5 days. These chemicals stimulate the cells in the bone marrow to move into the circulating blood system where they can be collected as a big blood sample through a line. This will take about 3 hours during which time the patient will stay in bed, but can read or watch television. Sometimes this procedure causes some dizziness and tingling in the fingers.

The choice of how the marrow cells are obtained is up to the leading clinician and depends on the patient’s characteristics. Harvesting the bone marrow will be chosen in patients who are under 5 years of age and/or weigh less than 10 kgs or who may not tolerate the stimulation procedure or have had a previous failure in the collection of peripheral blood stem cells.

For the gene therapy procedure, some bone marrow cells will be taken in the same way as described above. These bone marrow cells will be taken to a special gene therapy laboratory where the new gene will be put in. This will take three days, during which time the patient will receive some medicines to help the new bone marrow grow well. Then, the new bone marrow will be given just like a transfusion. This will take less than an hour. The patient needs to stay in hospital for several weeks until the bone marrow recovers. After this, regular blood samples will be taken to check how things are going and to look for infections.

Q. If someone has previously had gene therapy before can they still get involved?

It is very unlikely that a patient screened to be enrolled in the study had gene therapy previously to treat CGD or another disease. If such a case happens, it will analysed on a case to case basis.

Q. If someone has had a failed stem cell transplant can they take part?

Failure to a previous stem cells transplant is not an exclusion criterion for the study providing the patient fits the eligibility criteria.

Q. How many patients do you want to recruit?

The study is planned to recruit 20 patients over the 3 clinical centres.

Q. Who is funding the trial?

The study is coordinated by Genethon a not for profit French biotechnology laboratory and funding through the Net4CGD program which is a large-scale integrating project in Health Research of the European Commission 7th framework programme (FP7). The Net4CGD project is focused on the clinical development of a gene therapy as a new orphan drug. The aim is that this will rapidly become a new treatment option for patients with the X-linked form of CGD. The Net4CGD consortium consists of 11 partners Institutions and is coordinated by Genethon

Q. How many centres are involved and how are they working together?

Three clinical sites based in the UK, Germany and Switzerland will take part in the study. These sites work closely together and the results from each centre will be pooled for the final analysis.

Q. What are the advantages taking part?

If the treatment works, the bone marrow cells with the new gene will produce healthy cells in the bloodstream to cure pre-existing severe infections and to protect against further infections. This will lead in an improvement of the clinical well-being of patients

Q. Can Gene therapy be considered as a cure for CGD ?

Clinicians don't really like to use the word 'cure', particularly for new treatments which are being tested. However, the goal of the current trial is to produce an effective treatment that will last lifelong.

Q. Are there any disadvantages?

Apart from the usual risks linked to the Hematopoietic Stem Cell Transplant (HSCT), the specific risks due to the gene therapy are linked to the lentivirus carrying the new gene. The bone marrow cells will be given the new gene in a special laboratory while they are out of the body, so it is very unlikely that the virus can pass the new gene into cells such as egg or sperm cells. It has been specifically designed to target the stem cells that make blood. Nevertheless, as it is the case in all preliminary research, if applicable, patients must agree to use appropriate medically approved contraception during the trial and for 1 month after the end of the trial.

When the lentivirus enters the cell the new gene is inserted into the existing chromosomes so that it can be passed on to daughter cells when it divides. This is a random event and it is not known where exactly in the chromosomes the new gene will be placed. Because of this it is possible that the virus may affect the function of another gene. If it inserts near a cancer causing gene it may trigger the cell into a cancer cell and lead to leukaemia. In a few patients with X-CGD, and with other similar immunodeficiencies, this type of side effect has occurred after gene therapy using other types of virus. However this new lentivirus based gene therapy has been designed to help lower this risk to ensure it is safer, and to lessen the risk of this side effect. Although all the prior testing supports this idea, we can’t be fully sure until it is tested in patients. We therefore don’t know the actual risk, but we believe that it is much reduced. At the moment 13 patients have already been treated with lentivirus based systems and no serious adverse reaction to the virus and to the treatment has been reported with a follow up of more than 4 years. . Ethical and scientific committees have studied the safety profile of this vector and on the basis of many discussions have approved this study and have agreed that the treatment of X-CGD by gene therapy is promising, and that the potential risks should be balanced against the risks associated with alternative treatment by bone marrow transplantation.

Q. What will happen when the results of the trial are known?

When the results are known, the study will be published in a medical journal and the results presented in medical congresses.

The results of this trial will benefit the global research on CGD and on gene therapy. If the results are encouraging the trial will benefit patients with X-CGD and lacking a matched donor for HSCT.

Q. What are the study timelines?

The study has already been approved in all the participating countries and is currently running at the moment. The study is scheduled to finish by the end of 2017.

Q What is the follow-up to be received by an involved patient throughout the trial and afterwards ?

Following gene therapy, patients will be followed up on a monthly basis for 3 months, then quarterly for the 1st year and then twice yearly up to the 2nd year of participation.

Gene therapy being a new treatment approach that involves a permanent change in the genetic code of some patients cells, patients having received this treatment require a long term health monitoring. This long term monitoring will last for 3 additional yearly visits at 3, 4 and 5 years post gene therapy in addition to the two years period of monitoring described above. This long term follow up will allow the assessment of the long term safety profile of the gene therapy and collect additional data on the clinical status of the patients.

Q What is the possibility for a participant in the study to leave the study at any stage (even after the signature of informed consent) ?

The patient can leave the study at any time even after the signature of informed consent.

Q. Who do patients contact in the UK if they want to find out more?

The patients should contact the following clinical experts concerning participating in the study:

Prof Adrian Thrasher

Molecular Immunology Unit, UCL Institute of Child Health 30 Guilford Street

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Tel: 0044 207 905 2660
Fax: 0044 207 905 2810

Prof Bobby Gaspar

Molecular Immunology Unit, UCL Institute of Child Health 30 Guilford Street

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Tel: 0044 207 905 2319
Fax: 0044 207 905 2810