GENETIC RESEARCH
Epidermolysis Bullosa (EB) is a genetic condition affecting approximately 1:17,000 live births. In the UK there are an estimated 4-5,000 people with the condition, with around 300,000 worldwide. The condition is always painful, frequently very disabling and life threatening and, in its most severe forms, babies die within the first two years of life.
There are three distinct types of the condition, all with several sub groups, which vary greatly in appearance and prognosis. Some forms are inherited dominantly, i.e. where one parent has the condition and passes it on, and others have a recessive pattern of inheritance, i.e. both parents are unaffected carriers of the condition.
Despite the complexity of the condition, there has been an explosion of knowledge about the genetics of EB over the past 5-10 years. The genes that are responsible for all of the main forms of EB are now known and genetic material has been successfully altered in the laboratory to correct the defect in vitro. Much of the work that has accomplished this has been funded by DebRA as a result of collaborations with the leading research groups in Europe and, to a lesser extent, in the USA. As a result, EB is in the front rank of genetic conditions where there are realistic expectations of treatments being developed.
The challenge now facing EB research is to move towards the time when the defect can be altered in humans to alleviate or eliminate their symptoms. The challenge is different in the recessive and dominant forms. In the case of recessive EB, it is known that an increase in correctly functioning protein over a certain threshold will correct the symptoms. In dominantly inherited types of EB it has generally been believed to be necessary to knock out the defective gene since it will “overpower” any correctly functioning gene. However, recent data suggests that, if the defective protein can be suppressed sufficiently, symptoms can be eliminated.
Delivery of the modified gene is also a major challenge. Any delivery mechanism, known as a vector, must be safe, effective and targeted. Various different types of vector are being investigated and comparisons are planned.
Whilst these are significant challenges there is considerable optimism that they can be overcome. The first ever consensus meeting on EB was held in late 1999 as a result of a joint initiative between DebRA UK and DebRA of America, involving the leading researchers from Europe, the USA and Japan. This conference determined the key issues to be addressed in EB genetic research and encouraged the development of multi-national collaborations between research groups with a strong emphasis on the needs of the patient. The principles agreed at the meeting, which have been updated at two subsequent conferences, guide DebRA’s current genetic research programme. A further meeting is to be held in Ireland in October 2005.
CURRENT RESEARCH FUNDED OR ASSISTED BY DebRA UK
Gene Therapy Programme grants
Programme grants are longer term grants, involving several groups researching a number of linked issues, to promote a collaborative solution to the major problems of therapy development.
Details of these three projects can be found on the DebRA International website, under European Union Funded Research
RNA therapeutics for EB Simplex. Profs. Irwin McLean & Birgit Lane, University of Dundee. Therapeuskin. Ex vivo gene therapy for recessive dystrophic EB: preclinical studies. Prof Alain Hovnanian, INSERM U563, Toulouse et al Skintherapy. Gene therapy for EB: a model system for treatment of inherited skin diseases. Dr Guerrino Meneguzzi, INSERM 634, Nice et al
DebRA funds in full the grant to Profs. McLean and Lane to work on the development of gene therapy for EBS. Therapeuskin and Skintherapy are both programmes funded under the European Union Sixth Framework Programme to work on gene therapy for RDEB; DebRA is a partner in both programmes.
All of these programmes have the objective of finalising preclinical work on gene therapy for different forms of EB, prior to Phase I/II clinical trials.
Pre-Clinical Project grants
Details of the following research projects can be found on the DebRA International website, under Current Funded Research. Project grants, typically made for 1-3 years, fund work directed at investigating specific issues, judged by DebRA’s scientific advisers to be essential steps on the road to therapy.
EB Simplex
Investigation of fever-associated improvement in EBS. Prof. Birgit Lane, University of Dundee. Study of the mechanism behind the cell fragility of EBS. Prof. Birgit Lane, University of Dundee. Identification of mutations and mechanisms in EBS. Prof. Birgit Lane, University of Dundee. Generation of a mouse model for EBS-MD (EB Simplex with muscular dystrophy). Prof. Arnoud Sonnenberg, Netherlands Cancer Institute, Amsterdam. Developing spliceosome mediated RNA trans-splicing (SMaRT) for gene therapy in EB patients. Prof. Johann Bauer, Paracelsus Medical University, Salzburg. K15 keratin to the rescue of basal keratinocytes in EBS: use of thyroid hormones and interferon-gamma to increase specifically K15 gene transcription. Dr Miroslav Blumenberg, New York University School of Medicine.
Recessive dystrophic EB
Preclinical research project for ex vivo gene therapy for RDEB using COL7A1 expressing retroviral vectors. Prof. Alain Hovnanian, INSERM U563, Toulouse The influence of allogeneic fibroblasts on basement membrane zone composition in RDEB. Prof. John McGrath, St John’s Institute of Dermatology, London and Prof. Irene Leigh & Dr Harry Navsaria, Centre for Cutaneous Research, Barts & London School of Medicine & Dentistry. Preclinical gene therapy of RDEB. Dr Guerrino Meneguzzi, INSERM 634, Nice. Exploration of therapeutic approaches for EB. Dr Jane Farrar, Prof. Peter Humphries and Mr D Allen, Trinity College Dublin. (DEBRA Ireland project)
Junctional EB
Gene therapy of mild junctional EB. Dr Guerrino Meneguzzi, INSERM 634, Nice
Generic
Identification of novel genes involved in maintaining structural integrity of the cutaneous basement membrane zone. Dr Mahendra Sonawane, Max-Planck Institut fűr Entwicklungsbiologie, Tuebingen.
Kindler Syndrome: an inducible mouse model for gene therapy development. Prof. Irwin McLean, University of Dundee.
