BUBBLE foundation UK - Medical Research -

There are many different forms of immune deficiency and each requires dedicated research to aid early diagnosis and determine individual treatment to give each baby and child the best chance of survival. Over the past ten years, we have established a reputation as one of the top five research units in Europe and enjoyed the highest success rates in Europe for specific conditions.

We have an outstanding record of clinical achievement and an expanding programme with outreach clinics in Manchester, Edinburgh and Dublin. Over 1,400 immunodeficiency referrals are seen each year and the Unit performs 30 bone marrow transplants (BMT) annually for immunodeficiency. Indeed, we performed the first UK BMT for paediatric rheumatological conditions, as well as pioneering umbilical stem cell transplantation for immunodeficiency.

The growth in clinical activity has facilitated significant research activity, including substantial programmes investigating chronic mucocutaneous candidiasis and polysaccharide antibody deficiency following cardiac transplantation. Other studies have looked at markers for the early diagnosis of SCID, immunological defects in DiGeorge syndrome, gene mapping in osteopetrosis, and the elucidation of immunodeficiency due to DNA repair defects. The Unit has established the UK registry for chronic granulomatous disease and a European registry of BMD for CD 40 ligand deficiency. This last initiative highlights the Unit’s participation in collaborative European research, which has been funded by successive EU Biomed grants.

To date, we have:

achieved world-breaking results using stem cells to treat patients
pioneered use of umbilical cord blood to treat patients
established a national database for patients with a rare immunodeficiency and pioneered bone marrow transplantation for this disorder
investigated the development of the new immune system after transplantation
been involved in diagnosing of novel immunodeficiency and identification of the genetic cause of a further immunodeficiency
pioneered inhaled treatment to improve outcome of patients with lung inflammation post transplant and as a consequence most patients now survive

Importantly as a result of research to date, we have been able to pioneer treatment, which has saved the lives of babies and children.

The relocation of the University Department of Haematology laboratory has provided the opportunity to develop a world-class stem cell, marrow manipulation and gene therapy unit. To take the research forward, a senior academic member of staff is developing key projects, in collaboration with medical staff in genetics and haematology.

There are a number of projects which we are running and require further funding for or are planning to start in the near future

Uncovering the genetic causes of new forms of SCID.

Understanding the genetic causes of SCID has helped us improve our understanding of how these diseases present and also improve our treatment. We are currently searching for a new gene that causes a rare form of SCID. We have found the region in the human genome where the defect is likely to be but further work is required to find the gene and understand its function.

Investigating risk factors that lead to severe forms of SCID

We are investigating defects in the chemical messages that cells use to talk to each other which may be important in developing certain forms of SCID. Understanding differences in these chemical messages will help us improve our treatments for this particular form of SCID which currently has a very poor survivial rate.

New vaccines to boost immunity

Following a successful transplant,some children still have minor problems fighting bacteria that hide themselves by covering themselves in sugar. We are investigating this defect in greater detail so that we can find better ways of protecting children from infection.

Umbilical cord stem cell therapy

We have pioneered the highly successful use of umbilical cord stem cells to transplant young children with SCID. In order that many more children can benefit from this treatment,we need to be able to grow stem cells that are collected in the laboratory before transplanting them into older children and we are planning a project to investigate this.

1. A study to examine the function of regulatory T cells in patients with Di George syndrome. Di George syndrome is one of the most common primary immunodeficiencies in childhood affecting approximately 1:4000 children. Many of these children will suffer recurrent infection and increasingly we are recognising autoimmune disease as part of the disorder. This may manifest itself as thyroid dysfunction or arthritis but other manifestations are described. We know that in the immune system there are certain cells that act as ‘policeman’ to try and control abnormal immune responses and prevent the development of autoimmune disease. We have previously demonstrated that children with Di George syndrome have lower numbers of these regulatory T cells than normal children. We are planning to investigate whether these cells work normally and whether they have a normal population of cells or whether the population is restricted. This will be an MD project leading to a higher degree for a research registrar but will give us insight into the development of autoimmunity, not only in children with Di George syndrome, but also into other children and possibly adults. It may have relevance in patients developing autoimmune features following bone marrow transplantation such as Graft versus Host disease.

2. Molecular characterisation of <?xml:namespace prefix = st1 ns = "urn:schemas-microsoft-com:office:smarttags" />DNA repair disorders leading to primary immunodeficiency. This study is looking at disorders of mending damaged DNA which in some children can lead to profound immune deficiency and often requires bone marrow transplantation. We are looking at the mechanisms whereby these diseases develop and in particular are investigating the patients with undefined immunodeficiencies. This is an on-going project and we are currently setting up an international collaboration looking at the outcome of transplantation for these patients. This particular project will require funds for the laboratory technician and research associate involved in developing the techniques to investigate these patients more carefully.

3. Long term outcomes of haematopoietic stem cell transplantation for primary immunodeficiency in childhood. As more and more patients are surviving HSCT for primary immunodeficiency and living into adulthood, it is very important to document the long term effects of haematopoietic stem cell transplantation in order to further improve current treatments. We aim to describe accurately the long term outcomes of HSCT for primary immunodeficiency and relate these to defined risk factors. We will employ a research fellow to gage transplant outcomes in clinical, psychological and immunological domains including hearing, lung function, dental assessment, quality of life, evaluations and educational and psychological assessments and detailed immunological laboratory work up to evaluate long term immune reconstitution. As one of the largest transplant centres for primary immunodeficiency in Europe and with a follow up population of about 120 patients, we are well placed to perform this study.

4. Secretarial support. The academic secretary supports the administrative side of the research on the unit, including administering grants, preparing manuscripts, arranging overseas student fellowships, travel arrangements to conferences as well as providing significant administrative support to the running of the Bubble Foundation.

5. Bubble Foundation Fellowship. An ongoing fellowship, awarded annually to support upcoming doctors at the beginning of their research career with a one year fellowship to formulate a project, gather pilot data and apply for formal funding.

6. Molecular Genetics and Pathogenesis of Primary Immunodeficiency Diseases. Primary immunodeficiency diseases (PIDs) are a heterogeneous group of individually rare monogenic disorders that have a collective paediatric incidence of 1:2000 children. Despite major advances in diagnostics and therapy, PIDs remain challenging to manage clinically and are frequently life-limiting. Furthermore it has become clear that the phenotypic expression of PIDs may range widely, from severe combined immunodeficiency through narrow susceptibility to specific pathogens to autoimmunity and predisposition to malignancy. Around 150 PIDs have been defined at the molecular genetic level, with benefits for patient management as well as scientific understanding. The identification of causative mutations provides a basis for understanding the aetiology of the disease, offers the possibility of accurate diagnosis and guides the management of affected individuals and families. As human gene knockouts, these disorders can provide an ideal way of defining the function of immune system genes and the cells that express them. This project aims to determine the molecular genetics and pathogenesis of inherited PIDs by (1) identifying further disease-causing genes by combining the highly successful techniques of autozygosity mapping and whole exome sequencing, (2) investigating gene function appropriately and thereby (3) providing a rationale for improved therapy for affected individuals.