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 Europe 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 Programme grants
EB Simplex
RNA therapeutics for EB Simplex. Profs. Irwin McLean & Birgit Lane, University of
Dundee.
Recessive dystrophic EB
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.
Project grants
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.
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.
Inducible deletion of plectin in basal keratinocytes.
Prof. Gerhard Wiche, Max F Perutz Laboratories, Vienna.
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 fur Entwicklungsbiologie, Tuebingen.
Kindler Syndrome: an inducible mouse model for gene therapy
development.
Prof. Irwin McLean, University of Dundee.
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