Xeroderma Pigmentosum : A first

For the first time, researchers have succeeded in reconstructing skin in vitro using genetically corrected XP cells, thus opening up the prospect of tissue therapy for Xeroderma Pigmentosum.

Xeroderma Pigmentosum (XP): a rare condition
Handed down by recessive autosomal inheritance, the gene carrying this condition must be received from both parents for the child to fall victim to the illness, which is characterised by sensitivity to light, variations in pigmentation, early ageing of the skin and development of malignant tumours. These symptoms are due to the hyper-sensitivity of the cells to UV radiation as a result of defective DNA repair.

A complex repair system to restore the integrity of the genome
The cells of XP sufferers are deficient in terms of their nucleotide excision repair sys-tem, a biochemical mechanism whose purpose is to remove lesions in the DNA caused by UV radiation. To date, seven XP complementation groups (designated XP-A to XP-G) have been described. Each is distinguished from the others by the type of repair protein that is deficient. Some of these proteins recognise the lesion, others remove the mutated portion of the DNA, while still others add corrected portions of DNA. In the XP-C group, the most widespread in Europe and North Africa, the mutated XP-C gene codes for a protein that recognises lesions caused by UV light. Once it has detected a lesion, the protein attaches to it, leading to the fixation of other DNA repair proteins. This means that when the XPC protein is non-existent or when it functions poorly, the lesions in the DNA will not be recognised. The other proteins cannot meet up at the site of the lesion in order to repair it. The upshot is an accumulation of mutations in the DNA which then leads to skin cancer.

The XP model: relevant to the study of UV hypersensitivity
In 2001, a L'Oréal research team, in conjunction with a team from the French CNRS, succeeded in constructing skin models in vitro using fibroblasts and keratinocytes from XP-C patients, thus reconstructing a skin affected by this condition1. The XP derma and epidermis present specific morphological and biochemical fea-tures compared with tissues obtained from normal cells. One major characteristic is the invagination of the epidermis in the equivalent of the dermis. Following exposure to UV B, the XP model evidences persistent UV-caused DNA damage, indicating that the repair system is defective.

A protein that is functional following genetic correction of the XP cells
Since that time, the CNRS team at the Institut Gustave Roussy has carried out suc-cessful experiments in the genetic correction of keratinocytes from XP-C sufferers. To accomplish this, the researchers integrated the healthy XPC gene into the ge-nome of affected cells using a retrovirus that enables the normal XPC protein to be expressed2. L'Oréal research workers then reconstructed skin in vitro using the keratinocytes that had been transformed by the normal XPC gene3. They were able to demonstrate in this way that not only does the epidermis present a normal architecture in terms of stratification (the stacking of keratinocytes in distinct layers) and differentiation, but also that the skin reconstructed in vitro using these "corrected" cells behaves like normal skin when it is irradiated with UVB: the cells are capable of repairing their DNA. In skin affected by the condition, even in the absence of UV radiation, the XP-C keratinocytes suffer from anomalies in the cell cycle and overexpression of beta 1-integrin, a protein which regulates cell growth. These de-fects are also corrected when the affected cells are transformed by the healthy gene. These initial experiments in skin reconstruction using keratinocytes corrected in vitro for deficiency in functional XPC protein open up prospects for tissue therapy for type C Xeroderma Pigmentosum.

1 Bernerd F, Asselineau D, Vioux C, Chevallier-Lagente O, Bouadjar B, Sarasin A, Magnaldo T. Clues to epidermal cancer proneness revealed by reconstruction of DNA repair-deficient xeroderma pigmentosum skin in vitro. Proc Natl Acad Sci U S A. 2001 Jul 3; 98(14):7817-22
2 Arnaudeau-Begard C, Brellier F, Chevallier-Lagente O, Hoeijmakers J, Bernerd F, Sarasin A, Magnaldo T. Genetic correction of DNA repair-deficient/cancer-prone Xeroderma pigmentosum group C keratinocytes. Hum Gene Ther. 2003 Jul 1; 14(10):983-96
3 Bernerd F, Asselineau D, Frechet M, Sarasin A, Magnaldo T. Reconstruction of DNA Repair-deficient Xeroderma Pigmentosum Skin In Vitro: A Model to Study Hypersensitivity to UV Light. Photochem Photobiol. 2005 Jan. 81(1):19-24


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Xeroderma Pigmentosum : A first