This page gives an overview of the immunology department and the conditions treated at Great Ormond Street Hospital (GOSH). It provides information on one of the conditions treated, severe combined immunodeficiency (SCID), and details how the department measures its clinical outcomes for treatment with gene therapy.
Overview of the Immunology Department
The Immunology Department at GOSH offers a comprehensive diagnostic and treatment service for children up to the age of 16 years with suspected or confirmed primary immunodeficiency. Services are also provided for children with a variety of other immunological disorders (excluding allergy at present).
Primary immunodeficiency disorders (PIDs) form a group of rare disorders that vary widely in severity. The human body relies on the immune system – a uniquely complex family of specialised disease-fighting cells – to ward off attack from infectious agents, such as viruses and bacteria. Children with PIDs are compromised in their ability to fight these infections.
Those infants and children at the mild end of the PIDs spectrum can be affected by frequent minor infections, while the more severe PIDs lead to life-threatening infections and other life-limiting complications.
In some cases mild PIDs can resolve with increasing age, but in most cases these are lifelong disorders that require treatments to prevent infections and treat other complications, and in some cases need extensive treatment to correct the underlying problem.
The Immunology Department offers diagnosis and management of all degrees of severity of PID. Most referrals are received at a tertiary level from secondary paediatric units across the UK, but direct referrals from GPs are also accepted. International referrals are also received from a variety of countries.
Services provided include inpatient, outpatient and daycase services. Infants and children who are affected by the more severe PIDs may require in-patient care, and some require treatment by bone marrow transplantation (BMT).A small and highly selected group of children also undergo gene therapy procedures.
Severe combined immunodeficiency (SCID) is one of the PIDs treated at GOSH. SCID is the name given to a group of rare inherited genetic disorders which cause severe abnormalities of the immune system.
Overview of Severe Comibined Immunodeficiency (SCID) and treatment of SCID
SCID occurs when white blood cells, responsible for fighting infection, are missing or working poorly. Their absence or poor function results in serious and often life threatening infections. It means children are born with almost no functioning immune system of their own.
The first case of SCID was reported in 1950 and, following a number of isolated reports of affected children, the term SCID was introduced to describe the syndrome.
These children therefore need to be completely isolated in a sterile environment, giving rise to the common name for the condition – ‘boy in a bubble’ syndrome. SCID is estimated to affect between one in 50,000 and one in 100,000 live births (it is difficult to make precise estimates for each form of the disease, given the small number of cases seen).
Not all cases of SCID are identical but all children with SCID have poorly working immune systems and need protection from infection. The most common forms of SCID are X-linked SCID, which only affects boys followed by Adenosine Deaminase-Deficient SCID, which affects both boys and girls.
If there is a family history of SCID, it is possible to offer genetic counselling and in some cases pre-natal diagnosis for future pregnancies. This ensures that treatment can be commenced immediately after birth, enhancing long-term outcomes.
First signs of SCID
Sometimes, babies with SCID seem well at birth and for the following few weeks or months. This is because they are partly protected by antibodies passed from mother to baby across the placenta during the last few months of pregnancy.
The first signs of SCID generally occur within the first three to six months. As the baby's immune system is not working properly, they become highly susceptible to infection. The baby may suffer infections more frequently than other children – run of the mill problems such as coughs and colds will seem more severe and last longer than would usually be expected, requiring repeated and prolonged courses of treatment. Other symptoms include poor weight gain and diarrhoea.
In many cases parents will seek help from their GP because of repeated infections, poor weight gain and feeding problems. However, sometimes the first indication that a child has SCID can be serious infection in which the child has to be admitted to an intensive care unit for emergency treatment.
Depending on the type of SCID, it may be possible to diagnose or at least suspect the disorder by performing a simple blood test known as a full blood count. However, more specialised immune blood tests are required to confirm the diagnosis.
Treatment of SCID
Once SCID is suspected the child will be referred to a specialist centre for treatment. GOSH is one of two funded centres in the UK that treat children with SCID, and is one of the largest centres worldwide. This service is provided by a close collaboration between the Immunology Department and Bone Marrow Transplant Unit. Treatment is also available at Newcastle General Hospital.
Treatment initially involves medication with antibiotics, anti-fungal, and (in some cases) anti-viral medicines to protect against serious infection.The child will not be able to produce his/her own antibodies to fight infection, so replacement antibody (immunoglobulin) is given. The child may also need blood, platelet or plasma transfusions if they are very unwell.
Bone marrow transplant (BMT)
Children with SCID almost always need treatment by either BMT or in a few highly selected cases, gene therapy which both offer a long term cure for the disease.
BMT aims to replace the faulty immune system with an immune system from a healthy donor. Healthy bone marrow is rich in stem cells, from which all the cells of the immune system develop, and it is possible to take bone marrow from a healthy individual and give it by transfusion into the child with SCID.
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 less good. Fully-matched bone marrow donors are found for approximately one in five children.
Gene therapy
Over the last ten years gene therapy has been trialled and considered for children for whom there is not a matched bone marrow donor. Gene therapy aims to correct the underlying genetic abnormality causing SCID.
Gene therapy involves taking stem cells from the affected child's blood or bone marrow and then, under laboratory conditions, introducing a working copy of the gene into the child’s cells using gene transfer technology. Once corrected, the cells are returned a few days later by transfusion into the child. As in a BMT, these new stem cells find their way to the bone marrow where they start to produce healthy immune cells.
The following information provides evidence for the results of gene therapy for X-Linked SCID and Adenosine Demaninase-Deficient SCID.
How do we measure the results of treatment for SCID?
Before the advent of modern medication and treatment, most affected babies did not survive beyond their first year. Today doctors understand much more about SCID. Treatment is now available that can reduce the risk of serious infection, and in many cases, cure the disorder.
To measure the result of gene therapy disease free survival rates and overall survival rates are used.
Disease free survival is the number of patients that have survived with no disease after treatment. 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.
Overall Survival is the number of patients that have survived after treatment.
Results for gene therapy in x-linked SCID patients
Most recent results show that gene therapy at GOSH for patients with X-linked SCID has been successful for ten out of ten children, allowing them to gain good recovery in their immune system. These children have gone on to lead normal lives without restriction and able to attend school. One child regrettably developed leukaemia two years after treatment but is currently in remission.
Children continue on some medication, but five of the ten X-SCID patients no longer require immunoglobulin infusions.
The children are monitored regularly so that appropriate treatment can be given early if necessary. Since these initial trials, the way in which the new gene is transferred has been changed to try to ensure that it is safer, and to attempt to lessen the risk of side effects such as leukaemia..
Nine out of the ten patients treated have achieved disease free survival and overall survival for X-linked SCID treated by gene therapy is 100 per cent.
These results are comparable to results of other patient studies of gene therapy in Paris.
Alternative survival from BMT is documented since 1995 at around 72 to 73 per cent. Whilst there is a lot less experience and fewer numbers treated by gene therapy compared to BMT, these early results show that this alternative treatment provides good results.
The child followed for the longest time, nine years, still had functioning immune cells, showing that gene therapy works in the long-term.
Results for gene therapy in Adenosine Demaninase-Deficient SCID
Most recent results show that gene therapy at GOSH for patients with Adenosine Demaninase-Definicent SCID has been successful for four out of six children, allowing them to gain good recovery in their immune system. These children have gone on to lead normal lives without restriction and able to attend school.
Three of the four Adenosine Deaminase-Definicent SCID patients no longer require immunoglobulin.
Four out of the six patients treated have achieved disease free survival.
Overall survival for Adenosine Deaminase-Definicent SCID treated by gene therapy is 100%.
Worldwide, 30 children have received gene therapy for ADA-SCID, none of whom have died and 70 per cent of whom have seen a clear clinical benefit.
About the information
This information was taken from the following publications that were published in August 2011:
H. B. Gaspar, S. Cooray, K. C. Gilmour et al. Hematopoietic Stem Cell Gene Therapy for Adenosine Deaminase–Deficienticient Severe Combined Immunodeficiency Leads to Long-Term Immunological Recovery and Metabolic Correction. Science Translational Medicine, 24 August 2011: Vol. 3, Issue 97, p. 97ra80
H. B. Gaspar, S. Cooray, K. C. Gilmour et al. Long-Term Persistence of a Polyclonal T Cell Repertoire After Gene Therapy for X-Linked Severe Combined Immunodeficiency. Science Translational Medicine, 24 August 2011: Vol. 3, Issue 97, p. 97ra79
This information will be reviewed in June 2013 and updated where possible.
Great Ormond Street Hospital runs more gene therapy trials for immune deficiency in children than any other centre in the world. The work was funded by Great Ormond Street Hospital Children’s Charity, Wellcome Trust, The Primary Immunodeficiency Association and the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital.
Great Ormond Street Hospital Children's Charity has committed to supporting further work in this area, providing funds for new upgraded laboratories required to scale up the gene therapy programme, as well as a number of the leading researchers involved in the research, including Professors Gaspar and Thrasher.
With ongoing support, the research team hope to roll out the hospital’s gene therapy programme to a number of other diseases, allowing many more patients to be offered this ground-breaking new therapy as a front line approach.
Glossary
Primary immunodeficiency disorders (PIDs) are disorders in which part of the body's immune system is missing or does not function properly
Bone marrow transplantation (BMT) aims to replace the faulty immune system with an immune system from a healthy donor.
Gene therapy involves taking stem cells from an affected child's blood or bone marrow and then, under laboratory conditions, introducing a working copy of the gene into the child’s cells using gene transfer technology. Once corrected, the cells are returned a few days later by transfusion into the child.
Severe combined immunodeficiency (SCID) is one of the PIDs treated at GOSH. SCID is the name given to a group of rare inherited genetic disorders which cause severe abnormalities of the immune system.
X-Linked SCID 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 where in the body they mature, that is the thymus organ (T) and the bone marrow (B).
Adenosine Deaminase-Deficient 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.
Immunoglobulins is a solution of purified human antibodies which have been removed from normal blood donations. It provides temporary protection against infection and it is given either intravenously (into a vein) or subcutaneously (injection into the skin).
Transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood.
Disease free survival is the number of patients that have survived with no disease after treatment. 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.
Overall survival is the number of patients that have survived after treatment
Leukaemia a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts".
Great Ormond Street Hospital Children’s Charity (GOSHCC) needs to raise £50 million every year to help rebuild and refurbish Great Ormond Street Hospital, buy vital equipment and fund pioneering research. GOSHCC is also the UK’s largest charitable funder of medical research dedicated to paediatrics.
As well as providing long-term support for Great Ormond Street Hospital’s pioneering gene therapy programme, GOSHCC has committed to investing over £5m each year towards research to improve the health of children across the UK. GOSHCC has recently launched its Bringing Research to Life campaign to raise awareness and vital funds to support child health research – to find out more please visit: http://www.gosh.org/gen/bringingresearchtolife/
The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities.
The Trust’s breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests. www.wellcome.ac.uk
The National Institute for Health Research provides the framework through which the research staff and research infrastructure of the NHS in England is positioned, maintained and managed as a national research facility.
The NIHR provides the NHS with the support and infrastructure it needs to conduct first-class research funded by the Government and its partners alongside high-quality patient care, education and training. Its aim is to support outstanding individuals (both leaders and collaborators), working in world class facilities (both NHS and university), conducting leading edge research focused on the needs of patients
