RARE DISEASE
Xeroderma pigmentosum
Xeroderma pigmentosum
Xeroderma pigmentosum
Drug discovery
4
drugs
With orphan designations
Overview
Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder characterized by defective DNA repair mechanisms, leading to extreme photosensitivity, UV-induced skin cancers (10,000× higher risk), ocular damage, and progressive neurodegeneration in 20-30% of cases. Symptoms manifest in infancy with severe sunburns, freckling, and premature skin aging. Diagnosis relies on clinical features and genetic testing. Management focuses on rigorous UV avoidance, frequent cancer surveillance, and prompt lesion treatment. Median survival is 32 years, with metastatic skin cancer as the leading cause of death [1][4][11].
Therapies
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare neoplastic diseases, rare neurological diseases, rare ophthalmic disorders, rare skin diseases
Research Papers
1,224 drug discovery papers about Xeroderma pigmentosum, with 5 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,224 drug discovery papers about Xeroderma pigmentosum, with 5 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-11 | XPA confers ability of endonucleases to act processively and to incise damaged nucleosomal DNA
Repair of damaged DNA is a complex process, particularly when it is compacted into nucleosomes. There are a number of genetic disorders with deficiencies in DNA repair. Knowledge of the genes and proteins involved in these repair deficiencies is critical in developing an understanding of the molecular mechanisms utilized by proteins in the DNA repair pathways. One of these genetic disorders is xeroderma pigmentosum (XP), which is defective in nucleotide excision repair (NER). Patients in XP complementation group A (XP-A) are among the most severely affected with the lowest levels of DNA repair. The XPA protein, which is defective in these patients, plays a number of roles in the DNA repair process. One particularly important role proposed is acting as a processivity factor enabling endonucleases (XPF and XPG) and the XPB/TFIIH translocase to localize to damage sites using a processive mechanism of action. Another proposed role is in interacting with chromatin-remodeling proteins so as to enhance accessibility of lesions in nucleosomal DNA to endonucleolytic incision and other DNA repair activities. In XP-A cells, the XPA protein is proposed to be defective in ability to act as a processivity factor; endonucleases localize damage sites by a distributive mechanism and are also defective in incision of damaged nucleosomal DNA. This defect is corrected by recombinant normal human XPA. Mutations in exons 3 and 5 in the DNA binding domain of the XPA gene lead to loss of ability of XPA to act as a processivity factor. The mutation in exon 5 was found in two XP-A patients with severe XP. These studies emphasize the importance of correlating specific mutations in an XP gene and the resulting defect in a particular repair protein with the clinical severity of XP and could lead to development of novel therapeutic approaches for this disorder.
2026-07-14 | Unusual Presentation of Triple-Negative Breast Cancer in a Young Woman with Xeroderma Pigmentosum: A Case Report
Introduction: Xeroderma pigmentosum (XP) is a rare autosomal recessive DNA repair disorder, resulting from defects in nucleotide excision repair, that predisposes affected individuals to multiple cancers, particularly skin malignancies. Internal tumors including breast cancer are uncommon. Triple-negative breast cancer (TNBC) is an aggressive subtype that presents unique therapeutic challenges, particularly in XP patients where radiotherapy is contraindicated. Case Presentation: We report a a 34-year-old woman with XP who presented with a 6-cm right breast mass. Histopathology revealed grade III invasive carcinoma of no special type (NST) ER-negative, PR low-positivity (1–2% of cells), HER2-negative (Score 0), Ki-67 >80%. BRCA1/2 testing was negative. She underwent four cycles of neoadjuvant doxorubicin/cyclophosphamide with limited response, followed by modified radical mastectomy with axillary lymph node dissection. Pathology confirmed residual 60 mm tumor with negative surgical margins and fifteen negative lymph nodes. Pathological stage: pT3pN0M0 (AJCC 8th edition). She subsequently received adjuvant paclitaxel plus carboplatin. Radiotherapy was omitted due to XP-related radiosensitivity. At 12 months, the patient remained disease-free. Conclusion: TNBC in XP is exceedingly rare and presents complex management challenges. Platinum-based chemotherapy is biologically rational given the underlying NER defect and may be particularly effective given underlying DNA repair defects, while radiotherapy avoidance necessitates surgical prioritization and PARP inhibitors may represent promising future strategies.
2026-06-24 | Expert opinion
Keratinocyte carcinoma (KC), formerly known as non-melanoma skin cancer (NMSC), includes basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and their precursors such as actinic keratosis (AK) and Bowen’s disease, an in situ form of cSCC [ 1 ]. cSCC is the second most common form of skin cancer after BCC, accounting for approximately 20% of KC [ 2 , 3 ]. Determining its precise incidence is challenging; however, cSCC represents a growing public health concern, with recent data showing a sustained increase in incidence in Germany [ 4 ]. Known risk factors are fair or light skin, male sex, cumulative ultraviolet radiation exposure, history of severe sunburns, older age, systemic immunosuppression (including organ transplantation and hematologic malignancies such as chronic lymphocytic leukemia), smoking, and genetic predisposition such as xeroderma pigmentosum [ 5 , 6 , 7 ].
2026-06-16 | Development of rutin-loaded cerosomes for topical photoprotection and skin barrier modulation.
Xeroderma pigmentosum (XP) is a rare DNA-repair disorder associated with extreme photosensitivity, high skin cancer risk, progressive xerosis and barrier dysfunction. Current management relies largely on strict photoprotection, which does not address impaired hydration and epidermal barrier integrity. This work developed cerosomes (ceramide-containing vesicular systems) as multifunctional topical carriers combining barrier-replenishing ceramides with rutin as an antioxidant/photoprotective agent. Box-Behnken design was applied to optimize rutin-loaded cerosomes by evaluating phospholipid concentration, Tween®80:phospholipid ratio and ceramide concentration on the physicochemical properties. The optimized Tween® 80 formulation showed suitable attributes for topical delivery, with vesicle size <300 nm, polydispersity index <0.3, zeta potential <-30 mV, association efficiency >50% and loading capacity ∼0.8% but these were not maintained after 30 days at room-temperature. Surfactant substitution with Pluronic® F-127 or sodium deoxycholate improved storage stability up to 60 days, while rutin release was complete within 6 h and followed Fickian diffusion. In HaCaT keratinocytes, rutin-loaded cerosomes were cytocompatible up to 50-100 μM, while unloaded systems were more cytotoxic, suggesting a protective role of rutin. In vitro photoprotection assays showed that Pluronic®-stabilized cerosomes increased SPF to 40 vs 25 obtained with blank sunscreen, and improved photostability up to 60 min of simulated UV exposure. Barrier-related performance was supported by film-forming/occlusive effects, as well as modulation of water loss and theophylline permeation across artificial membranes and intact/damaged skin models. These findings support rutin-loaded cerosomes as a promising nanoplatform for combined photoprotection and barrier-oriented care in XP.
2026-06-03 | Engineering quantum dot surfaces to preserve protein-DNA interactions for single-molecule visualization.
Quantum dots (QDs) are fluorescent nanoparticles widely used for single-molecule imaging because of their exceptional brightness and photostability. However, the impact of QD surface chemistry on biomolecular interactions has not been systematically investigated. Here, we report that commercial QDs unexpectedly destabilize protein-DNA complexes by inducing protein dissociation from DNA. Using the human nucleotide excision repair protein, xeroderma pigmentosum complementation group A (XPA) as a model system, we demonstrate that antibody-conjugated QDs promote dissociation of XPA from DNA substrates, independently of sizes and surface modification of QDs, antibody types, epitope tags, buffer conditions, or DNA structures. We find that polyethylene glycol (PEG), a common polymer coating on QD surfaces, is the primary factor responsible for this effect. To tackle this problem, we engineered QDs with precisely controlled surface polymer compositions. By systematically changing the ratio of anchoring, hydrophilic, and PEG-based functional groups, we find that reducing PEG density below a critical threshold effectively suppresses protein dissociation while maintaining excellent colloidal stability and brightness. Furthermore, antibodies conjugated via click chemistry between azide groups and DBCO enabled specific labeling of XPA without perturbing the DNA binding activity. Using these optimized QDs, we conducted single-molecule DNA curtain assays to visualize XPA-DNA interactions. QD-labeled XPA exhibits one-dimensional diffusion with frequent pausing on undamaged DNA. DNA curtain assays revealed that XPA preferentially binds DNA bubbles and searches for bubble structures through both one-dimensional diffusion and three-dimensional collision. Quantitative analysis showed that three-dimensional collision is the dominant pathway for bubble recognition. Taken together, our results uncover a previously unrecognized limitation of PEG-coated QDs in single-molecule studies and provide an improved surface-engineering strategy to preserve native protein-DNA interactions. Newly engineered QDs establish robust platforms for accurate single-molecule visualization of biomolecular processes.
2026-08-11 | XPA confers ability of endonucleases to act processively and to incise damaged nucleosomal DNA
Repair of damaged DNA is a complex process, particularly when it is compacted into nucleosomes. There are a number of genetic disorders with deficiencies in DNA repair. Knowledge of the genes and proteins involved in these repair deficiencies is critical in developing an understanding of the molecular mechanisms utilized by proteins in the DNA repair pathways. One of these genetic disorders is xeroderma pigmentosum (XP), which is defective in nucleotide excision repair (NER). Patients in XP complementation group A (XP-A) are among the most severely affected with the lowest levels of DNA repair. The XPA protein, which is defective in these patients, plays a number of roles in the DNA repair process. One particularly important role proposed is acting as a processivity factor enabling endonucleases (XPF and XPG) and the XPB/TFIIH translocase to localize to damage sites using a processive mechanism of action. Another proposed role is in interacting with chromatin-remodeling proteins so as to enhance accessibility of lesions in nucleosomal DNA to endonucleolytic incision and other DNA repair activities. In XP-A cells, the XPA protein is proposed to be defective in ability to act as a processivity factor; endonucleases localize damage sites by a distributive mechanism and are also defective in incision of damaged nucleosomal DNA. This defect is corrected by recombinant normal human XPA. Mutations in exons 3 and 5 in the DNA binding domain of the XPA gene lead to loss of ability of XPA to act as a processivity factor. The mutation in exon 5 was found in two XP-A patients with severe XP. These studies emphasize the importance of correlating specific mutations in an XP gene and the resulting defect in a particular repair protein with the clinical severity of XP and could lead to development of novel therapeutic approaches for this disorder.
2026-07-14 | Unusual Presentation of Triple-Negative Breast Cancer in a Young Woman with Xeroderma Pigmentosum: A Case Report
Introduction: Xeroderma pigmentosum (XP) is a rare autosomal recessive DNA repair disorder, resulting from defects in nucleotide excision repair, that predisposes affected individuals to multiple cancers, particularly skin malignancies. Internal tumors including breast cancer are uncommon. Triple-negative breast cancer (TNBC) is an aggressive subtype that presents unique therapeutic challenges, particularly in XP patients where radiotherapy is contraindicated. Case Presentation: We report a a 34-year-old woman with XP who presented with a 6-cm right breast mass. Histopathology revealed grade III invasive carcinoma of no special type (NST) ER-negative, PR low-positivity (1–2% of cells), HER2-negative (Score 0), Ki-67 >80%. BRCA1/2 testing was negative. She underwent four cycles of neoadjuvant doxorubicin/cyclophosphamide with limited response, followed by modified radical mastectomy with axillary lymph node dissection. Pathology confirmed residual 60 mm tumor with negative surgical margins and fifteen negative lymph nodes. Pathological stage: pT3pN0M0 (AJCC 8th edition). She subsequently received adjuvant paclitaxel plus carboplatin. Radiotherapy was omitted due to XP-related radiosensitivity. At 12 months, the patient remained disease-free. Conclusion: TNBC in XP is exceedingly rare and presents complex management challenges. Platinum-based chemotherapy is biologically rational given the underlying NER defect and may be particularly effective given underlying DNA repair defects, while radiotherapy avoidance necessitates surgical prioritization and PARP inhibitors may represent promising future strategies.
2026-06-24 | Expert opinion
Keratinocyte carcinoma (KC), formerly known as non-melanoma skin cancer (NMSC), includes basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and their precursors such as actinic keratosis (AK) and Bowen’s disease, an in situ form of cSCC [ 1 ]. cSCC is the second most common form of skin cancer after BCC, accounting for approximately 20% of KC [ 2 , 3 ]. Determining its precise incidence is challenging; however, cSCC represents a growing public health concern, with recent data showing a sustained increase in incidence in Germany [ 4 ]. Known risk factors are fair or light skin, male sex, cumulative ultraviolet radiation exposure, history of severe sunburns, older age, systemic immunosuppression (including organ transplantation and hematologic malignancies such as chronic lymphocytic leukemia), smoking, and genetic predisposition such as xeroderma pigmentosum [ 5 , 6 , 7 ].
2026-06-16 | Development of rutin-loaded cerosomes for topical photoprotection and skin barrier modulation.
Xeroderma pigmentosum (XP) is a rare DNA-repair disorder associated with extreme photosensitivity, high skin cancer risk, progressive xerosis and barrier dysfunction. Current management relies largely on strict photoprotection, which does not address impaired hydration and epidermal barrier integrity. This work developed cerosomes (ceramide-containing vesicular systems) as multifunctional topical carriers combining barrier-replenishing ceramides with rutin as an antioxidant/photoprotective agent. Box-Behnken design was applied to optimize rutin-loaded cerosomes by evaluating phospholipid concentration, Tween®80:phospholipid ratio and ceramide concentration on the physicochemical properties. The optimized Tween® 80 formulation showed suitable attributes for topical delivery, with vesicle size <300 nm, polydispersity index <0.3, zeta potential <-30 mV, association efficiency >50% and loading capacity ∼0.8% but these were not maintained after 30 days at room-temperature. Surfactant substitution with Pluronic® F-127 or sodium deoxycholate improved storage stability up to 60 days, while rutin release was complete within 6 h and followed Fickian diffusion. In HaCaT keratinocytes, rutin-loaded cerosomes were cytocompatible up to 50-100 μM, while unloaded systems were more cytotoxic, suggesting a protective role of rutin. In vitro photoprotection assays showed that Pluronic®-stabilized cerosomes increased SPF to 40 vs 25 obtained with blank sunscreen, and improved photostability up to 60 min of simulated UV exposure. Barrier-related performance was supported by film-forming/occlusive effects, as well as modulation of water loss and theophylline permeation across artificial membranes and intact/damaged skin models. These findings support rutin-loaded cerosomes as a promising nanoplatform for combined photoprotection and barrier-oriented care in XP.
2026-06-03 | Engineering quantum dot surfaces to preserve protein-DNA interactions for single-molecule visualization.
Quantum dots (QDs) are fluorescent nanoparticles widely used for single-molecule imaging because of their exceptional brightness and photostability. However, the impact of QD surface chemistry on biomolecular interactions has not been systematically investigated. Here, we report that commercial QDs unexpectedly destabilize protein-DNA complexes by inducing protein dissociation from DNA. Using the human nucleotide excision repair protein, xeroderma pigmentosum complementation group A (XPA) as a model system, we demonstrate that antibody-conjugated QDs promote dissociation of XPA from DNA substrates, independently of sizes and surface modification of QDs, antibody types, epitope tags, buffer conditions, or DNA structures. We find that polyethylene glycol (PEG), a common polymer coating on QD surfaces, is the primary factor responsible for this effect. To tackle this problem, we engineered QDs with precisely controlled surface polymer compositions. By systematically changing the ratio of anchoring, hydrophilic, and PEG-based functional groups, we find that reducing PEG density below a critical threshold effectively suppresses protein dissociation while maintaining excellent colloidal stability and brightness. Furthermore, antibodies conjugated via click chemistry between azide groups and DBCO enabled specific labeling of XPA without perturbing the DNA binding activity. Using these optimized QDs, we conducted single-molecule DNA curtain assays to visualize XPA-DNA interactions. QD-labeled XPA exhibits one-dimensional diffusion with frequent pausing on undamaged DNA. DNA curtain assays revealed that XPA preferentially binds DNA bubbles and searches for bubble structures through both one-dimensional diffusion and three-dimensional collision. Quantitative analysis showed that three-dimensional collision is the dominant pathway for bubble recognition. Taken together, our results uncover a previously unrecognized limitation of PEG-coated QDs in single-molecule studies and provide an improved surface-engineering strategy to preserve native protein-DNA interactions. Newly engineered QDs establish robust platforms for accurate single-molecule visualization of biomolecular processes.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
4 orphan drug designations for Xeroderma pigmentosum.
4 orphan drug designations for Xeroderma pigmentosum.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Afamelanotide | peptides | EMA | 2024-05-24 | — | Clinuvel Europe Limited |
Pro-Pro-Thr-Val-Pro-Thr-Arg | peptides | FDA | 2017-07-27 | — | ProGeLife S.A.S |
PRO-PRO-THR-VAL-PRO-THR-ARG [INHOX] | peptides | EMA | 2014-11-19 | — | ProGeLife S.A.S. |
T4 endonuclease V, liposome encapsulated | proteins | FDA | 1989-06-27 | — | AGI Dermatics |
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