GENE THERAPY FOR EPIDERMOLYSIS BULLOSA
BETWEEN HOPES AND
REALITY
The current state of progress in 2001 Prof Alain Hovnanian |
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Prof Alain Hovnanian is the Wellcome Trust Senior Clinical Fellow at the
Wellcome Trust Centre for Human Genetics, University of Oxford; and Professor of Genetics,
Department of Medical Genetics, University of Toulouse, France.
He is the lead
Co-ordinator of the new international and collaborative research |
programme
being funded by DebRAwhich commenced in February 2001. This is a concerted research programme
for the development of ex vivo gene therapy for Recessive Dystrophic EB. This involves six
groups, Prof Alain Hovnanian in Oxford and Toulouse, Profs Robin Eady and John McGrath at St
Thomas' in London, Prof Leena Bruckner-Tuderman in Munster, Germany, Prof Irene Leigh and
Dr Liz Rugg at St Bartholomew's & The Royal London School of Medicine &
Dentistry, Dr Zoia Larin at the University of Oxford and Dr Olivier Danos at the Genethon in
France. |
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Introduction
The
identification of the defective genes in the different forms of epidermolysis bullosa (EB)
has raised new hopes for the treatment of EB by gene therapy. Encouraging results have
been obtained, although there is still no treatment currently available. In October 1999,
the first DebRA international visioning / consensus meeting on EB was held in New Jersey.
A number of recommendations have been made aiming at joining research efforts on gene
therapy for the different forms of EB.
What
is gene therapy?
Gene therapy aims at treating a disease by correcting
its genetic defect.
Most often, it involves the transfer of a copy of the
normal gene into the cells, as replacement of the mutated copy is much more difficult to
achieve. For these reasons, recessive disorders are usually more amenable to gene therapy
than dominant diseases.
Gene therapy through
the skin or by skin graft?
Gene therapy for EB points at correcting the genetic defect within the cells of the
epidermis (outer layer of the skin). As the epidermis is a continually renewing tissue,
the cells which have the potential to multiply most (stem cells) need to be corrected to
prevent loss of the new gene.
However, these cells are located deep in the epidermis, and therefore are difficult to
target by direct gene delivery through the skin (in vivo approach). In contrast, they can
be isolated from a skin biopsy, grown in the laboratory and used as targets for genetic
transfer in culture.
Once corrected, these cells can be expanded in cultures of epithelial sheets and used to
graft patients in selected areas (ex vivo approach).
Which gene-transfer vector?
Several viral and non viral vectors have been developed to introduce genes of interest
within cells. Each has its own advantages and disadvantages, but retroviral vectors are
currently the most efficient systems to transfer genes into chromosomes. Chromosomal
integration or maintenance of a stable episome are required for transmission of the new
gene to daughter cells.
Gene therapy can be successful
in humans.
Very recently, several patients with a severe genetic
immunodeficiency were cured after genetic transfer of a normal copy of the defective gene
into bone marrow cells using a retroviral vector.
This first demonstration of successful
ex vivo gene therapy in human suggests that similar results could also be achieved in EB.
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