Genetic therapy of Xeroderma Pigmentosum: analysis of strategies and translation

ABSTRACT

Introduction: Xeroderma Pigmentosum (XP) is among the rare genetic disorders remaining without any cure. XP patients bear mutations in one of the eight genes involved in either the repair or the tolerance of DNA lesions induced following UV irradiation by the mechanism of nucleotide excision or of translesion synthesis. Irrespective of their appurtenance to either the “classical groups of genetic complementation (XP-A to XP-G), or to the variant form of the disease (XP-V), all patients clinically diagnosed as “XP” present with severe photo sensitivity and a high susceptibility toward aggressive skin cancers.

Areas covered: Only few palliative ‘treatments’ can currently be proposed to these patients, among which sun avoidance remains the most efficient recommendation to prevent onset of skin cancers. Early clinical and genetic diagnosis is essential to optimize the care of XP patients. Attempts to genetically correct XP cells by retrovirus-mediated gene transfer have been successful, and held promises for ex vivo cutaneous gene therapy of XP cells using retrovirus-mediated transfer of the therapeutic (XP) gene.

Expert commentary: However, bona fide genetic correction by recent techniques of genome edition, for instance using the CRISPR-CAS 9 technology, may appear even more attractive in the future. Taking into account the different facets of the disease in its different forms, we discuss the potential therapeutic approaches that could help improving life conditions of those rare patients who still lack any efficient cure.

KEYWORDS:

• Xeroderma Pigmentosum
• skin
• NER
• cancer
• gene therapy

Article highlights

• Xeroderma Pigmentosum (XP) is a rare, autosomal and recessive genetic disorder remaining without a cure.

• XP patients mostly suffer from hypersensitivity to ultraviolet (UV) sunlight wavelengths and, early in life, development of skin cancers in photo exposed skin areas.

• The XP disease is due to constitutive defect in repair or replicative tolerance of DNA lesions after UV exposure.

• Current therapeutics are mostly limited to sun avoidance and tumor ablation.

• Genetic correction of XP epidermal stem cells based on gene transfer led to phenotypic normalization of DNA repair defect.

• In combination with genetic correction of epidermal cells, pharmacological strategies are also considered to limit permissive effects of XP skin microenvironment which cancers development in XP patients.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by the French Government (National Research Agency, ANR; CNRS; INSERM) through the ‘Investments for the Future’ LABEX SIGNALIFE: program reference # ANR-11-LABX-0028-01; UNS (Université de Nice Sophia Antipolis) and Association René Tourraine. MGM was supported by the Fondation de l’Avenir (PhD fellowship 2015); TM was supported by the Fondation ARC (SFI201212055859), the Fondation de l’Avenir, the Société Française de Dermatologie, and The Institut National du Cancer. L’Oréal Recherche is acknowledged for exclusive financial support of the in vitro experiments performed in this study.