Gene therapy halts 'bubble boy' immune disease

Thursday August 25 2011

Today it has been widely reported that gene therapy offers a long-term treatment for a rare condition that causes children’s immune systems to fail. In the rare condition, known as Severe Combined Immunodeficiency (SCID), inherited genetic mutations mean that babies are unable to fight off infection, severely limiting their chances of surviving more than a few years.

However, researchers have now unveiled results of trial that show that gene therapy was succesful in 14 out of the 16 UK children they treated, allowing them to recover to lead normal lives. The technique works by introducing a working copy of the mutant gene, which provides the body with instructions on how to produce working immune system cells. The child followed for the longest time, nine years, still had functioning immune cells, showing that gene therapy works in the long-term.

Prior to gene therapy the only other option for children with the most common form of SCID was to receive a bone marrow transplant, which relied on finding a suitable match. This new technique, while not without risk, offers a credible treatment option in cases where a suitable donor cannot be found.

The news also highlights the potential for using gene therapy to treat a number of other genetic conditions, although it should be emphasised that there is no guarantee that these diseases can be treated as successfully.

Why is gene therapy for SCID in the news?

Doctors and researchers from the Institute of Child Health and Great Ormond Street hospital yesterday published research papers describing the long-term outcomes of gene therapy for children born with SCID. Their two papers, published in the journal Science Translational Medicine, describe positive long-term outcomes for the majority of the children they treated with gene therapy, who have been able to lead relatively normal lives since receiving treatment. Before gene therapy was available, children with the most common form of SCID would have been reliant on bone marrow transplants to help them survive. This was a troublesome prospect as the majority of children with the condition cannot find a fully-matched donor.

The results genuinely seem to represent a cure for most patients treated, hence the positive news reports from The Daily Telegraph, the Daily Mail and television news sources. The coverage featured in both newspapers is generally accurate, although neither paper mentions the complications seen in patients with X-linked SCID after gene therapy. That said, the results certainly warrant positive coverage.

What is SCID?

Severe combined immunodeficiency (SCID) is a rare genetic disorder estimated to affect between 1 in 200,000 and 1 in 1,000,000 live births (it is difficult to make precise estimates for each form of the disease, given the small number of cases seen). The condition results in a highly compromised immune system, leaving individuals with SCID extremely vulnerable to infectious diseases. David Vetter, a boy with SCID, lived for 12 years in a plastic, germ-free bubble, which is why the condition is also referred to as “bubble boy” disease by the press and public.

Affected infants are usually diagnosed due to severe infections, failure to thrive and a profile of immune cells consistent with SCID. Without treatment, individuals with the disease normally die within the first year of life. Prior to gene therapy, the only treatment option available was to perform bone marrow transplants, a procedure that in itself carries risk for children with SCID.

SCID can be caused by mutations in a number of genes. The most common form of SCID is X-linked SCID, which only affects boys. It is caused by a mutation in a protein required for the development and differentiation of two types of white blood cell that protect the body from infection, the T and B lymphocyte cells. These cells are named according to the where in the body they mature, i.e. the thymus organ (T) and the bone marrow (B).

The second-most common form of SCID is caused by mutations that compel the body to make an abnormal form of an enzyme called adenosine deaminase, which leads to a reduction in immune cell production. Other forms of SCID include Omenn syndrome, bare lymphocyte syndrome, and SCID caused by mutations in JAK3 and Artemis/DCLRE1C genes. Again, these are all extremely rare.

How would SCID traditionally be treated?

As mentioned earlier, bone marrow transplantation is a treatment option for SCID. In a transplant, healthy haematopoietic stem cells are given to the patient from a donor. Haematopoietic stem cells are very early blood cells which can differentiate and divide into all possible types of mature immune cells, including the B and T lymphocyte cells. Being able to make working B and T lymphocytes provides transplant patients with some level of protection against infection.

Bone marrow transplantation is most successful if a fully-matched family donor is available. It is also possible from matched unrelated donors and mismatched donors, although long-term survival is reduced. It’s estimated that only one in five children finds a fully-matched bone marrow donor.

Specific therapies for some of the different types of SCID are also available. For example, individuals with SCID caused by mutations in the adenosine deaminase enzyme can be treated with enzyme replacement therapy. However, immune function recovery is variable with this treatment.

How does gene therapy for SCID work?

Gene therapy for SCID works by correcting the genetic mutation in the hematopoietic stem cells (required for all immune cells) of the affected individual. Cells are removed from the patient’s bone marrow and, using special viral material, scientists introduce a functioning copy of the faulty gene that causes SCID. The corrected cells are then re-transplanted into the patient, and can use this functioning copy of the gene as a blueprint for making working immune system cells.

Chemotherapy is also performed in some cases. Chemotherapy may provide an initial advantage to the corrected cells and create space in the bone marrow, therefore improving incorporation of the corrected cells.

As this technique uses only cells taken from the affected individual, it does not carry the risk of illness caused by the body reacting to donor material. There’s also a reduced risk of the graft itself being rejected.

How successful was the new treatment?

In the two longer-term follow-up studies recently published in Science Translational Medicine, the underlying genetic defect was repaired in four out of six patients with Adenosine Demaninase-Deficient SCID, and 10 out of 10 patients with X-linked SCID. Immune cell production was restored, and the effects persisted up to nine years after therapy (the most recent point of measurement). The procedure produced minimal side effects, and patients could attend typical schools.

Combining the results with the results of other studies shows that 30 patients with Adenosine Demaninase-Deficient SCID have been treated with gene therapy to date. All patients have survived (follow-up of 1-10 years) and 21 (67%) have been able to stop enzyme replacement therapy. The authors of the London study conclude that “these cumulative data with such a high level of safety and efficacy argue strongly that gene therapy should be considered as the first treatment option when no matched family donor is available”.

The results for trials for gene therapy for X-linked SCID performed in England, France and Italy have also shown it to be effective/effective within the course of trials.

Are there any drawbacks/dangers?

The major danger is that gene therapy may activate an oncogene. These are genes (often a mutated form of a normal gene) that cause cancer. In the London trial, one of the 10 children treated for X-linked SCID developed leukaemia. He was treated with chemotherapy and is now in remission. Leukaemia also developed in four patients in the French trial. However, no cases of leukaemia have been observed in any of the 30 patients treated with gene therapy for Adenosine Demaninase-Deficient SCID. It is unclear whether this occurrence is due to the nature of the DNA inserted to correct the mutation, the nature of the condition itself or some other factor.

‘Next generation’ retroviral and lentiviral vectors (carriers for introducing new genes) are being developed to reduce the risk of leukaemia. At present, clinical trials using these vectors are commencing in Europe and the United States.

Could gene therapy be used for other conditions?

Gene therapy could potentially be used to treat a variety of genetic diseases. On the basis of the results of gene therapy for SCID, a broad array of blood cell diseases are being approached with gene therapy, including Wiskott-Aldrich syndrome, chronic granulomatous disease, X-adrenoleukodystrophy, metachromatic leukodystrophy, Huler’s syndrome and β-thalassemia. However, it is not certain that the same level of success would be achieved for these conditions. It is necessary to wait for disease-specific research to shed light on the issue.

Analysis by Bazian
Edited by NHS Choices