Abstract
Xeroderma pigmentosum (XP) is a rare autosomal recessive disease due to impaired nucleotide excision repair (NER) that results in severe sun sensitivity, a 10,000-fold risk of developing skin cancers, and - in 25-30% of cases - central nervous system degeneration. This review offers a thorough assessment of the molecular mechanism of XP, its multi-organ clinical symptoms, and critically reviews emerging and clinically tested therapeutic approaches, such as gene therapy, topical DNA repair enzymes and the new melanocortin agonist afamelanotide. We reviewed the literature for clinical trials, randomized controlled trials, and studies into the molecular mechanisms from 2000 to 2025. The results of this review show that while rigorous sun protection is the mainstay of treatment, new phase II clinical trials have shown that afamelanotide reduces the formation of cyclobutane pyrimidine dimers and could reduce the development of skin cancer. Topical T4N5 endonuclease (Dimericine) was promising but further efficacy studies were halted due to lack of long term efficacy. Gene therapy using XPA-corrected autologous keratinocytes and HVJ liposome to deliver XPA have demonstrated proof-of-concept in mice, but have yet to be translated to humans. Neuro complications lack disease-modifying therapies, and are an unmet need. Overall, XP remains a fatal disease, but there are promising new therapies that target disease-causing pathways with the first reported clinical reduction in DNA damage. Multimodal strategies to treat both skin and neurological aspects are required.