Xeroderma Pigmentosum (XP) is an uncommon autosomal recessive condition that is exceptionally sensitive to ultraviolet (UV) rays and associated with significantly higher chances of developing skin cancers, neurological disorders, and eye complications. Protheragen is leading the way in preclinical research as well as therapeutic development for XP focusing on the molecular disease mechanisms and accelerating the application of innovative concepts into clinical practice.
With a global incidence of one in a million, XP arises due to mutations in excision repair genes XPA-XPG and XPV. This refractive disorder results in hypersensitivity to UV radiation. XP patients exhibit extreme reaction to sun exposure including significant burns accompanied by intense freckling. Depending on age, these individuals can develop melanomas or squamous cell carcinoma at an estimated 10,000 times more than the general population. Furthermore, neurodegenerative changes accompany accelerated photodamage.
The underlying causes of XP stem from mutagenic alterations within coding regions responsible for DNA repair—namely the NER pathway or DNA polymerase η—which prevents proper removal of UV-induced DNA lesions. As a result, XP patients display heightened genomic instability alongside severe collagen diploidy which correlate with aggressive malignancies of the skin coupled with progressive cognitive decline.
Fig.1 Overview of the nucleotide excision repair (NER) process and frequencies of genes affected in Xeroderma pigmentosum (XP). (Martens, Emmert and Boeckmann, 2021)| Therapeutic Strategy | Target / Intervention | Key Findings / Rationale | Development Stage |
| Afamelanotide | Melanocortin-1 Receptor (MC1R) | Stimulates melanogenesis; enhances DNA repair capacity | Phase II |
| T4 Endonuclease V (T4N5) Liposomes | Cyclobutane pyrimidine dimers | Bacterial DNA repair enzyme; excises UV-induced DNA lesions | Phase III |
| Nicotinamide | PARP/NAD+ pathway | Boosts DNA repair; inhibits UV-induced immunosuppression | Phase II |
| Melatonin | Oxidative stress/Neuroprotection | Antioxidant; reduces neuronal DNA damage | Preclinical to Phase I |
| Acetohexamide (Repurposed) | NER pathway activation | Small molecule activator of nucleotide excision repair | Preclinical |
| Gene Editing | XPC/XPA/XPD genes | Corrects pathogenic mutations in DNA repair genes | Preclinical |
| Autologous Stem Cell Gene Therapy | DNA repair machinery | Lentiviral delivery of functional DNA repair genes (e.g., XPC) to HSCs | Preclinical |
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.
Protheragen provides the complete service of developing therapies for rare skin diseases such as Xeroderma pigmentosum. Our specialists, including scientists, dermatologists, and geneticists, formulate therapeutic and disease model to support all research project phases.
Protheragen excels in developing custom 2D cell models, 3D skin models and animal models, and animal models that accurately mimic XP's etiology, characterized by defective DNA repair, increased UV sensitivity, and accelerated carcinogenesis. These models are invaluable for therapeutic testing and validation.
In Vivo Pharmacokinetics Services
Protheragen specializes in cutting-edge preclinical research services. Utilizing our integrated discovery platforms, we accelerate therapeutic development for rare cutaneous disorders like Xeroderma pigmentosum. Our innovative proprietary disease models, alongside comprehensive drug safety evaluation and DMPK services, facilitate a seamless progression from target validation to IND-enabling studies.
If you are interested in our services, please feel free to contact us.
References
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