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
1,229 drug discovery papers about Xeroderma pigmentosum, with 5 first-in-class and 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
1,229 drug discovery papers about Xeroderma pigmentosum, with 5 first-in-class and 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-28 | Identification of an ERCC2 Mutation-Associated Mutational Signature of Nucleotide Excision Repair Deficiency in Targeted Panel Sequencing Data.
Next-generation sequencing-based mutational signatures are frequently used to identify tumors with specific DNA repair deficiencies for targeted therapeutic strategies. Although mutational signatures are commonly derived from whole-exome or whole-genome sequencing data, patients often undergo tumor sequencing using more limited targeted panels that typically encompass several hundred cancer-associated genes. Identifying clinically relevant mutational signatures from targeted panel data requires new approaches capable of deriving signatures from the more limited sequencing data. Using publicly available panel sequencing data, we derived and validated a panel sequencing-based composite mutational signature associated with nucleotide excision repair (NER) deficiency induced by inactivating ERCC2 mutations in bladder cancer. We found that ERCC2 wild-type (WT) bladder cancer cases that have high levels of this mutational signature respond better to neoadjuvant platinum therapy and have improved overall survival compared with ERCC2 WT cases with low levels of the signature. We also found that other solid tumor types with ERCC2 mutations also show the characteristic mutational signature seen in NER-deficient ERCC2-mutant bladder cancers, suggesting a novel approach to therapeutically target these ERCC2-mutant solid tumors beyond bladder cancer. Mutational signature-based NER deficiency status can be determined in panel sequencing data of tumor biopsies. This could be used to investigate the connection between NER deficiency and response to neoadjuvant platinum-based chemotherapy.
2026-08-01 | EP1391 - ECE_3025 - Xeroderma pigmentosum: an underrecognized cause of premature ovarian insufficiency
Abstract Introduction Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder caused by mutations affecting one of seven genes involved in the DNA repair pathway, leading to hypersensitivity to the deleterious effects of ultraviolet (UV) radiation on DNA. From a gynecological and endocrine perspective, women with XP appear to be at increased risk of developing premature ovarian insufficiency (POI). We report the case of a 29-year-old woman with XP who presented with secondary amenorrhea, in whom investigations revealed POI. Case Report A 29-year-old woman with xeroderma pigmentosum diagnosed in childhood presented with secondary amenorrhea of one year's duration. Menarche occurred at the age of 13 years, with regular menstrual cycles until the age of 24 years, followed by the onset of oligo-spaniomenorrhea and subsequently secondary amenorrhea associated with hot flashes from the age of 28 years. Hormonal evaluation revealed hypergonadotropic hypogonadism with low estradiol and markedly elevated FSH and LH, associated with a severely reduced ovarian reserve (AMH <0.01 ng/mL), consistent with premature ovarian insufficiency. Karyotype analysis was normal. Discussion This case highlights a rarely described association between xeroderma pigmentosum, a DNA repair–deficiency disorder, and premature ovarian insufficiency, highlighting the essential role of genomic stability in preserving normal ovarian function. The ovaries, due to their high proliferative activity, exhibit particularly high expression levels of the XPC gene, likely reflecting an increased requirement for correction of replication errors and repair of endogenous DNA damage. Murine models of XP demonstrate reduced reproductive performance, associated with increased apoptosis of germ cells. Merideth et al. (2019) evaluated 60 women with xeroderma pigmentosum and found that 31% of these patients had experienced menopause, with 78% meeting criteria for premature menopause; the median age at menopause was 29.5 years, approximately 20 years earlier than in the general population. Conclusions Awareness of the increased risk of premature menopause in women with xeroderma pigmentosum warrants early surveillance to detect declining ovarian reserve and to guide reproductive management. When indicated, initiation of hormone replacement therapy is essential to prevent skeletal and cardiovascular complications.
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.
2026-06-16 | 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.
proteins
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.
2026-04-11 | Clinicopathological and molecular characterization of tumor-associated macrophages in sporadic and Xeroderma Pigmentosum-related cutaneous melanoma.
BACKGROUND: Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder, resulting from genetic defects in the nucleotide excision repair (NER) pathway. It predisposes individuals to skin cancers, including melanoma. The melanoma microenvironment is enriched with inflammatory mediators, particularly macrophages, which may serve as prognostic biomarkers or therapeutic targets. While inflammation is linked to melanoma outcomes, its role in carcinogenesis among XP patients remains poorly understood. METHODS: We assessed the cytokine profiles in the sera of XP-melanoma patients, as well as the expression level of a pan-macrophage marker (CD68), M2-markers CD163, and M1-associated nitric oxide synthase (iNOS) expression. RESULTS: XP patients exhibited significantly reduced levels of iNOS, MIP-1β, MCP-1, and IL-33, indicating an impaired inflammatory and macrophage-mediated immune response. We also found that IL-33 and iNOS levels were positively correlated with the density of inflammatory infiltrates. Moreover, in vitro assays using G361 melanoma cells demonstrated that both pro-inflammatory macrophage-conditioned media and exogenous IL-33 suppressed tumor cell proliferation. CONCLUSION: This study emphasizes the need for specific macrophage biomarkers and proposes local interleukin-33 delivery as a potential therapy for poorly infiltrated melanoma. This also suggests that NER-deficient patients may exhibit unique molecular profiles, warranting personalized treatment.
2025-01-08 | Beyond Nucleotide Excision Repair: The Importance of XPF in Base Excision Repair and Its Impact on Cancer, Inflammation, and Aging.
DNA repair involves various intricate pathways that work together to maintain genome integrity. XPF (ERCC4) is a structural endonuclease that forms a heterodimer with ERCC1 that is critical in both single-strand break repair (SSBR) and double-strand break repair (DSBR). Although the mechanistic function of ERCC1/XPF has been established in nucleotide excision repair (NER), its role in long-patch base excision repair (BER) has recently been discovered through the 5'-Gap pathway. This study briefly explores the roles of XPF in different pathways to emphasize the importance of XPF in DNA repair. XPF deficiency manifests in various diseases, including cancer, neurodegeneration, and aging-related disorders; it is also associated with conditions such as Xeroderma pigmentosum and fertility issues. By examining the molecular mechanisms and pathological consequences linked to XPF dysfunction, this study aims to elucidate the crucial role of XPF in genomic stability as a repair protein in BER and provide perspectives regarding its potential as a therapeutic target in related diseases.
2024-03-25 | Generation of site-specifically labelled fluorescent human XPA to investigate DNA binding dynamics during nucleotide excision repair.
Nucleotide excision repair (NER) promotes genomic integrity by removing bulky DNA adducts introduced by external factors such as ultraviolet light. Defects in NER enzymes are associated with pathological conditions such as Xeroderma Pigmentosum, trichothiodystrophy, and Cockayne syndrome. A critical step in NER is the binding of the Xeroderma Pigmentosum group A protein (XPA) to the ss/ds DNA junction. To better capture the dynamics of XPA interactions with DNA during NER we have utilized the fluorescence enhancement through non-canonical amino acids (FEncAA) approach. 4-azido-L-phenylalanine (4AZP or pAzF) was incorporated at Arg-158 in human XPA and conjugated to Cy3 using strain-promoted azide-alkyne cycloaddition. The resulting fluorescent XPA protein (XPACy3) shows no loss in DNA binding activity and generates a robust change in fluorescence upon binding to DNA. Here we describe methods to generate XPACy3 and detail in vitro experimental conditions required to stably maintain the protein during biochemical and biophysical studies.
2023-03-16 | DNA repair in cardiomyocytes is critical for maintaining cardiac function in mice.
Heart failure has reached epidemic proportions in a progressively ageing population. The molecular mechanisms underlying heart failure remain elusive, but evidence indicates that DNA damage is enhanced in failing hearts. Here, we tested the hypothesis that endogenous DNA repair in cardiomyocytes is critical for maintaining normal cardiac function, so that perturbed repair of spontaneous DNA damage drives early onset of heart failure. To increase the burden of spontaneous DNA damage, we knocked out the DNA repair endonucleases xeroderma pigmentosum complementation group G (XPG) and excision repair cross-complementation group 1 (ERCC1), either systemically or cardiomyocyte-restricted, and studied the effects on cardiac function and structure. Loss of DNA repair permitted normal heart development but subsequently caused progressive deterioration of cardiac function, resulting in overt congestive heart failure and premature death within 6 months. Cardiac biopsies revealed increased oxidative stress associated with increased fibrosis and apoptosis. Moreover, gene set enrichment analysis showed enrichment of pathways associated with impaired DNA repair and apoptosis, and identified TP53 as one of the top active upstream transcription regulators. In support of the observed cardiac phenotype in mutant mice, several genetic variants in the ERCC1 and XPG gene in human GWAS data were found to be associated with cardiac remodelling and dysfunction. In conclusion, unrepaired spontaneous DNA damage in differentiated cardiomyocytes drives early onset of cardiac failure. These observations implicate DNA damage as a potential novel therapeutic target and highlight systemic and cardiomyocyte-restricted DNA repair-deficient mouse mutants as bona fide models of heart failure.
gene therapies
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 ].
2026-06-01 | HX08 From ‘children who burn in sunlight’ to DNA repair defect: xeroderma pigmentosum and the birth of molecular dermatology
Abstract In the late nineteenth century, Hebra and Kaposi described children whose skin developed severe pigmentation, scarring and ulceration after minimal exposure to sunlight. These patients frequently developed multiple skin cancers in early childhood and often died young. The condition, later termed xeroderma pigmentosum (XP), was clinically recognizable but biologically unexplained. For much of the early 20th century, XP was managed as an extreme photosensitivity disorder. Treatment consisted almost entirely of avoidance: strict sun protection, protective clothing and social isolation. Care focused on shielding patients from injury rather than understanding the mechanism. As later commentators noted, management relied on environmental restriction rather than biological explanation. A fundamental shift occurred in 1968, when Cleaver demonstrated that cells from patients with XP were unable to repair ultraviolet-induced DNA damage. This discovery established XP as the first human disease directly linked to a defect in DNA repair. The skin was no longer viewed as unusually sensitive; it was genetically incapable of correcting environmental injury. With this finding, dermatology entered the molecular era. The implications extended far beyond a rare genodermatosis. XP provided direct evidence that cancer could result from failure of genomic maintenance. DNA repair disorders became models for carcinogenesis, revealing a fundamental principle of cancer biology. This insight transformed care. Modern management of XP includes early genetic diagnosis, rigorous cancer surveillance, chemoprevention and multidisciplinary support. Patients are no longer defined by isolation, but by proactive protection and counselling. The history XP illustrates dermatology’s unique contribution to molecular medicine. A rare childhood condition reframed ultraviolet radiation as a mutagen and the skin as a site of genomic vulnerability. XP demonstrates how careful attention to cutaneous disease can uncover mechanisms that reshape all of medicine, marking one of dermatology’s clearest transitions from descriptive specialty to molecular science.
2026-03-01 | 301P Early access program of birabresib in NUT carcinoma patients
Background: Rare malignancies arising in genetic cancer syndromes, chronic inflammatory states, congenital anomalies, therapy-related settings, and those with unusual paraneoplastic or metastatic patterns represent a distinct, under-reported subgroup Here we are presenting 37 such rare malignancies due to the rarity and for documentation.Methods: This retrospective observational study included 37 patients treated between January 1998 and August 2025 at a tertiary cancer center in Eastern India.Eighteen cases had been previously published and 19 new cases were added.Patients were categorized into: (1) common malignancies arising in rare genetic or acquired predisposing conditions, and (2) common malignancies with rare clinical, biological, paraneoplastic, or metastatic manifestations.Results: Patients with xeroderma pigmentosum (n=6) had squamous, basal cell and malignant melanomas with tongue and ovarian carcinoma, Tuberous sclerosis (n=4) had SEGA and bilateral renal angiomyolipomas.Neurofibromatosis (n=7) had malignant peripheral nerve sheath tumors and intracranial tumors, hereditary multiple exostoses (n=1) had chondrosarcomaa nd Klinefelter syndrome (n=1) had CML.Malignancies arising in chronic states were SCC over burn scars (n=3), filarial scrotum (n=1), tropical ulcer (n=1), adenocarcinoma in ectopia vesicae (n=1).Therapy-related second cancer were meningioma 12 years after childhood ALL and AML 63 months after CTRT for cancer cervix. 2 patients had primary granulocytic sarcoma of meninges and mediastinum.Paraneoplastic syndromes included carcinoma larynx with pemphigus, bronchial carcinoid with ectopic cushing's syndrome and solitary fibrous tumor with hypoglycemia.Rare associations included vanishing bone disease, ectopic male breast cancer on the upper chest wall, synchronous GIST with papillary RCC, synchronous Lobular carcinoma of breast with clear cell carcinoma of right kidney and colonic metastasis from IDC of the breast.Conclusions: Due to the rarity lifelong surveillance, early genetic counseling, prompt evaluation of chronic non-healing lesions, and structured survivorship follow-up are essential to improve outcomes in high-risk populations.
2026-02-06 | [Clinical characterization and genetic analysis of a patient with Xeroderma pigmentosum in conjunct with basal cell carcinoma and melanoma due to variants of XPC gene].
To explore the clinical presentation and genetic etiology of a case with Xeroderma pigmentosum in conjunct with basal cell carcinoma and melanoma. A male patient with Xeroderma pigmentosum treated at Xinxiang Central Hospital in October 2022 was selected as study subject. Whole exome sequencing (WES) was carried out. Candidate variants were verified by Sanger sequencing of his family members. This study was approved by the Ethics Committee of the hospital (Ethics No.: 2021-167). Magnetic resonance imaging showed that the patient has a solid soft tissue mass in the anterior and lower part of his right eyeball and a small nodule on the left nasal wing. Histopathological biopsy showed that the periocular tumor was basal cell carcinoma in conjunct with malignant melanoma, and the nasal wing tumor was basal cell carcinoma. WES and Sanger sequencing revealed that he has harbored compound heterozygous variants of the XPC gene, namely c.2391delT (p.F797Lfs*11) and IVS1+1G>A, which were inherited from his father and mother, respectively. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variants were rated as likely pathogenic (PVS1+PM2_Supporting+PM3) and pathogenic (PVS1+PM2_Supporting+PM3+PP5), respectively. The c.2391delT variant was unreported previously. Bioinformatic analysis suggests that it could significantly affect the tertiary structure of XPC protein. The c.2391delT(p.F797Lfs*11) and IVS1+1G>A compound heterozygous variants probably underlay the pathogenesis in this patient. The detection of the novel variant has enriched the mutational spectrum of the XPC gene.
2026-02-04 | Arabidopsis XPD functions upstream of CDKA;1 to regulate stomatal development.
In eukaryotes, XERODERMA PIGMENTOSUM GROUP D (XPD) is an integral subunit of the DNA repair/transcription complex TFIIH. In animals, XPD has been implicated in TFIIH-independent complexes regulating cell division, which, however, remains poorly understood in plants. Here, we identified XPD as a novel regulator of stomatal development in Arabidopsis. Its loss-of-function mutants exhibited increased stomatal precursor cells and formed stomatal clusters. Genetic analysis showed that XPD functions upstream of SPEECHLESS (SPCH) to control stomatal lineage entry, coordinates with MUTE to regulate meristemoid division and works together with FLP and FAMA to restrict GMC division. In a search of XPD interactors, we identified CDKA;1, which serves as both an essential cyclin-dependent kinase and a key SPCH activator. Consistently, xpd mutants exhibited enhanced stomatal lineage cell divisions and elevated SPCH protein levels. Furthermore, XPD acts upstream of CDKA;1, as expression of the dominant-negative CDKA;1.N146 allele significantly suppressed the excessive cell division and stomatal development defects in xpd plants. Our data highlight the precise regulation of stomatal development by XPD, expanding its critical TFIIH-independent roles in plant cell division and fate specification.
oligonucleotides
2025-11-17 | Expanding the landscape of nucleotide excision repair disorders: from discovery to therapy.
DNA damage and repair are central to the onset of cancer, aging, and aging-related diseases. Rare genetic defects in the nucleotide excision repair pathway, such as those causing the cancer-prone disorder xeroderma pigmentosum (XP) or the progeroid condition Cockayne syndrome, highlight the dramatic consequences of unrepaired DNA lesions. In this issue of the JCI, two related papers from Ogi and coworkers - Fassihi et al. and Nakazawa et al. - describe a new XP clinical entity, XP-J, linked to a pathogenic variant in the p52 subunit of the transcription-repair complex TFIIH. The studies' characterization of XP-J and the p52ΔC variant opened unexpected possibilities to ameliorate the molecular defect in another subunit of TFIIH that causes a different, more severe repair syndrome: trichothiodystrophy. This commentary provides a broader historical, medical, and molecular context for the intricate genotype-phenotype relationship between compromised repair and its clinical consequences and discusses next steps for the advances reported.
2025-09-09 | TFIIH-p52ΔC defines a ninth xeroderma pigmentosum complementation-group XP-J and restores TFIIH stability to p8-defective trichothiodystrophy.
Few drugs are available for rare diseases due to economic disincentives. However, tailored medications for extremely rare disorders (N-of-1) offer a ray of hope. Artificial antisense oligonucleotides (ASOs) are now best known for their use in spinal muscular atrophy (SMA). The success of nusinersen/Spinraza for SMA indicates the potential of ASO therapies for other rare conditions. We propose a strategy to develop N-of-1 ASOs for treating one form of trichothiodystrophy (TTD), a rare condition with multisystem abnormalities and reduced life expectancy, associated with instability and greatly reduced amounts of the DNA-repair/transcription factor TFIIH. The therapeutic targets carry mutations in GTF2H5, encoding the TFIIH-p8 subunit. This approach was inspired by the diagnosis and molecular dissection of a xeroderma pigmentosum (XP) case with mutations in GTF2H4, encoding the TFIIH-p52 subunit. This is newly classified as a ninth XP complementation-group, XP-J, identified 5 decades after the discovery of the other XP complementation-groups. The p8-p52 interaction is required to support the TFIIH-complex formation, and the patient's p52 C-terminal truncation results in the complete absence of p8 in TFIIH. However, intriguingly, TFIIH remained stable in vivo, and the patient with XP-J did not exhibit any TTD-features. The aim of our ASO-design is to induce a C-terminal truncation of p52 and we have successfully stabilized TFIIH in p8-deficient cells from patients with TTD-A.
2023-06-28 | Deep intronic founder mutations identified in the ERCC4/XPF gene are potential therapeutic targets for a high-frequency form of xeroderma pigmentosum.
Xeroderma pigmentosum (XP) is a genodermatosis defined by cutaneous photosensitivity with an increased risk of skin tumors because of DNA repair deficiency. The worldwide prevalence of XP is ~1 to 4 in million, with higher incidence in some countries and regions including Japan (1 in 22,000) and North Africa due to founder mutations and a high degree of consanguinity. Among XP, the complementation group F (XP-F), is a rare form (1% of worldwide XP); however, this is underdiagnosed, because the ERCC4/XPF gene is essential for fetal development and most of previously reported ERCC4/XPF pathogenic variants are hypomorphs causing relatively mild phenotypes. From the largest Japanese XP cohort study, we report 17 XP-F cases bearing two pathogenic variants, both identified in deep intronic regions of the ERCC4/XPF gene. The first variant, located in intron 1, is a Japanese founder mutation, which additionally accounts for ~10% of the entire Japanese XP cases (MAF = 0.00196), causing an aberrant pre-mRNA splicing due to a miss-binding of U1snRNA. The second mutation located in intron eight induces an alternative polyadenylation. Both mutations cause a reduction of the ERCC4/XPF gene expression, resulting in XP clinical manifestations. Most cases developed early-onset skin cancers, indicating that these variants need critical attention. We further demonstrate that antisense oligonucleotides designed for the mutations can restore the XPF protein expression and DNA repair capacity in the patients' cells. Collectively, these pathogenic variants can be potential therapeutic targets for XP.
2019-06-21 | Nucleotide excision repair of abasic DNA lesions
Apurinic/apyrimidinic (AP) sites are a class of highly mutagenic and toxic DNA lesions arising in the genome from a number of exogenous and endogenous sources. Repair of AP lesions takes place predominantly by the base excision pathway (BER). However, among chemically heterogeneous AP lesions formed in DNA, some are resistant to the endonuclease APE1 and thus refractory to BER. Here, we employed two types of reporter constructs accommodating synthetic APE1-resistant AP lesions to investigate the auxiliary repair mechanisms in human cells. By combined analyses of recovery of the transcription rate and suppression of transcriptional mutagenesis at specifically positioned AP lesions, we demonstrate that nucleotide excision repair pathway (NER) efficiently removes BER-resistant AP lesions and significantly enhances the repair of APE1-sensitive ones. Our results further indicate that core NER components XPA and XPF are equally required and that both global genome (GG-NER) and transcription coupled (TC-NER) subpathways contribute to the repair.
2010-03-01 | Targeting and processing of site‐specific DNA interstrand crosslinks
Abstract DNA interstrand crosslinks (ICLs) are among the most cytotoxic types of DNA damage, and thus ICL‐inducing agents such as cyclophosphamide, melphalan, cisplatin, psoralen, and mitomycin C have been used clinically as anticancer drugs for decades. ICLs can also be formed endogenously as a consequence of cellular metabolic processes. ICL‐inducing agents continue to be among the most effective chemotherapeutic treatments for many cancers; however, treatment with these agents can lead to secondary malignancies, in part due to mutagenic processing of the DNA lesions. The mechanisms of ICL repair have been characterized more thoroughly in bacteria and yeast than in mammalian cells. Thus, a better understanding of the molecular mechanisms of ICL processing offers the potential to improve the efficacy of these drugs in cancer therapy. In mammalian cells, it is thought that ICLs are repaired by the coordination of proteins from several pathways, including nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR), homologous recombination (HR), translesion synthesis (TLS), and proteins involved in Fanconi anemia (FA). In this review, we focus on the potential functions of NER, MMR, and HR proteins in the repair of and response to ICLs in human cells and in mice. We will also discuss a unique approach, using psoralen covalently linked to triplex‐forming oligonucleotides to direct ICLs to specific sites in the mammalian genome. Environ. Mol. Mutagen. 2010. © 2010 Wiley‐Liss, Inc.
other
2026-08-27 | Clinics, Genetics and Treatment in a Russian Cohort of Young Patients with Xeroderma Pigmentosum: A Single Center Experience
Xeroderma pigmentosum (XP) and Cockayne syndrome (CS) are rare autosomal recessive DNA repair disorders. XP is characterized by extreme sensitivity to UV-radiation and a very high risk of skin cancer. To date, little is known about the clinical characteristics and genetic basis of these diseases in Russia. Here, we present a detailed study of 14 patients (aged 5–30 years) from 11 unrelated families of diverse ethnic backgrounds. Using a multigene panel or whole-genome sequencing, we identified homozygous or compound heterozygous variants in XPC (8 patients) and XPA (3 patients). In one family with two XP cases, a patient with CS and compound heterozygous ERCC6 variants was identified. In total, 110 family members were screened to determine their carrier status. Skin cancer was revealed in 12/13 (92%) of XP patients, with a median age at diagnosis of 12.5 years (range 5–22). Basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma developed in 10, 6, and 3 patients, respectively. All three cancer types occurred in 2 patients. All patients underwent surgical treatment; additionally, two patients with BCC received targeted therapy (vismodegib, sonidegib). Anti-PD-1 immunotherapy was administered with a favorable clinical response in three patients with advanced SCC or melanoma.
2026-05-23 | Synergistic enhancement of PD-L1 expression from DNA repair dysfunction and UV exposure in xeroderma pigmentosum: Potential therapeutic role of PD-L1 inhibitors.
Xeroderma pigmentosum (XP) is a rare genetic disorder caused by defective nucleotide excision repair, leading to extreme UV sensitivity and early-onset skin cancers. Although PD-1/PD-L1 inhibitors have shown benefit in XP-associated tumors, the mechanisms that underpins these therapeutic responses remains unclear. To elucidate the molecular basis of XP pathogenesis in a 4-year-old Filipino girl and to investigate the potential role of PD-L1 inhibitors in treating XP-associated squamous cell carcinoma (SCC). A 4-year-old girl with XP underwent germline whole-exome sequencing. Transcriptomic profiling and immunochemistry validation were performed on XP-SCC and non-XP SCC tissues. In vitro assays using HaCaT keratinocytes evaluated DNA damage and PD-L1 expression following XPA knockdown and UV radiation. A Jurkat-HaCaT co-culture system, incorporating a PD-L1 neutralizing antibody, assessed T-cell attachment. A homozygous splice-site variant in XPA (c.556-1 C>G) was identified. RNA-seq revealed marked up-regulation of CD274 (PD-L1), PDCD1 (PD-1), and STAT1 in XP-SCC. In vitro, XPA-deficient keratinocytes exhibited increased UV-induced DNA damage and synergistic PD-L1 induction. Jurkat T-cell attachment was elevated in UV-exposed, XPA-deficient groups; crucially, this enhanced attachment was significantly abolished by PD-L1 blockade. XPA deficiency and UV-induced stress jointly enhance PD-L1 expression in XP-associated cSCC. These molecular and functional data provide biologic rationale for PD-L1-targeted therapy in XP and support further evaluation of immune checkpoint inhibitors in this population.
2026-04-23 | Efficacy of immune checkpoint inhibitors in patients with xeroderma pigmentosum and advanced cutaneous squamous-cell carcinoma and literature review.
Xeroderma pigmentosum (XP) is a disorder characterized by defective DNA repair, leading to the early development of cutaneous malignancies, including cutaneous squamous cell carcinomas (cSCC). The management of locally advanced and metastatic cSCC in XP patients is particularly challenging, primarily due to the risk of major surgical sequelae and the hazardous use of radiotherapy. This study aims to evaluate the efficacy and safety of anti-PD1 immunotherapy in XP patients with unresectable cSCC in Mayotte and Réunion Island and to conduct a literature review. This retrospective multicenter study included XP patients treated with anti-PD1 for advanced or metastatic inoperable cSCC between June 2023 and February 2025. The efficacy and safety of the treatment were assessed based on clinical, biological, and radiological data from patient records. A literature review of similar cases was also conducted. Four XP patients, with a median age of 16 years, were treated with immunotherapy for cSCC or sarcomatoid carcinoma, achieving rapid and complete tumour regression in all cases. No major adverse effects were reported. The literature review identified 14 additional cases, including 7 complete responses and 6 partial responses. Anti-PD1 therapy is effective in XP patients with advanced cSCC, offering a therapeutic alternative to surgery. These findings raise the question of earlier neoadjuvant initiation to reduce the risk of major surgical sequelae or prevent metastatic progression.
2026-04-08 | Long‐Term Clinical Response After Low‐Dose and Short‐Duration Cemiplimab Therapy in a Patient With Xeroderma Pigmentosum in Nepal
ABSTRACT Xeroderma pigmentosum (XP), an autosomal recessive condition affecting DNA repair, is associated with a high risk of multiple and aggressive cutaneous squamous cell carcinomas (CSCCs). Because of numerous and/or locally advanced tumors, surgery may be difficult. The immune checkpoint inhibitor cemiplimab has been approved in advanced, unresectable, and/or metastatic CSCCs. However, it is not available everywhere and is typically inaccessible to the poor without health insurance. We hereby report our experience of using low‐dose and short‐duration treatment with cemiplimab in a 15‐year‐old male with XP and multiple advanced CSCCs. The patient showed a complete or partial response to all tumors. The therapy was subsequently stopped after eight pulses due to the COVID‐19 pandemic. The response lasted for 5 years without subsequent treatment, after which one of the tumors recurred and the new ones developed. Checkpoint inhibitors were no longer available at this time.
2026-01-21 | Pembrolizumab therapy leads to resolution of lentigines and tumour control in a patient with xeroderma pigmentosum and advanced cutaneous squamous cell carcinoma
We describe a 54-year-old patient with xeroderma pigmentosum (XP) who developed unresectable cutaneous squamous cell carcinoma and was treated with pembrolizumab, an immune checkpoint inhibitor (ICI). The treatment led to significant tumour regression and, unexpectedly, a complete resolution of the patient’s lentigines, while vitiligo and other pigmented lesions remained unchanged. The findings suggest that ICIs may amplify immune responses against ultraviolet-induced pigmented lesions in patients with XP, potentially linked to the disease’s high mutational burden. Further studies are needed to elucidate the underlying mechanisms.
small molecules
2026-09-28 | Identification of an ERCC2 Mutation-Associated Mutational Signature of Nucleotide Excision Repair Deficiency in Targeted Panel Sequencing Data.
Next-generation sequencing-based mutational signatures are frequently used to identify tumors with specific DNA repair deficiencies for targeted therapeutic strategies. Although mutational signatures are commonly derived from whole-exome or whole-genome sequencing data, patients often undergo tumor sequencing using more limited targeted panels that typically encompass several hundred cancer-associated genes. Identifying clinically relevant mutational signatures from targeted panel data requires new approaches capable of deriving signatures from the more limited sequencing data. Using publicly available panel sequencing data, we derived and validated a panel sequencing-based composite mutational signature associated with nucleotide excision repair (NER) deficiency induced by inactivating ERCC2 mutations in bladder cancer. We found that ERCC2 wild-type (WT) bladder cancer cases that have high levels of this mutational signature respond better to neoadjuvant platinum therapy and have improved overall survival compared with ERCC2 WT cases with low levels of the signature. We also found that other solid tumor types with ERCC2 mutations also show the characteristic mutational signature seen in NER-deficient ERCC2-mutant bladder cancers, suggesting a novel approach to therapeutically target these ERCC2-mutant solid tumors beyond bladder cancer. Mutational signature-based NER deficiency status can be determined in panel sequencing data of tumor biopsies. This could be used to investigate the connection between NER deficiency and response to neoadjuvant platinum-based chemotherapy.
2026-08-01 | EP1391 - ECE_3025 - Xeroderma pigmentosum: an underrecognized cause of premature ovarian insufficiency
Abstract Introduction Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder caused by mutations affecting one of seven genes involved in the DNA repair pathway, leading to hypersensitivity to the deleterious effects of ultraviolet (UV) radiation on DNA. From a gynecological and endocrine perspective, women with XP appear to be at increased risk of developing premature ovarian insufficiency (POI). We report the case of a 29-year-old woman with XP who presented with secondary amenorrhea, in whom investigations revealed POI. Case Report A 29-year-old woman with xeroderma pigmentosum diagnosed in childhood presented with secondary amenorrhea of one year's duration. Menarche occurred at the age of 13 years, with regular menstrual cycles until the age of 24 years, followed by the onset of oligo-spaniomenorrhea and subsequently secondary amenorrhea associated with hot flashes from the age of 28 years. Hormonal evaluation revealed hypergonadotropic hypogonadism with low estradiol and markedly elevated FSH and LH, associated with a severely reduced ovarian reserve (AMH <0.01 ng/mL), consistent with premature ovarian insufficiency. Karyotype analysis was normal. Discussion This case highlights a rarely described association between xeroderma pigmentosum, a DNA repair–deficiency disorder, and premature ovarian insufficiency, highlighting the essential role of genomic stability in preserving normal ovarian function. The ovaries, due to their high proliferative activity, exhibit particularly high expression levels of the XPC gene, likely reflecting an increased requirement for correction of replication errors and repair of endogenous DNA damage. Murine models of XP demonstrate reduced reproductive performance, associated with increased apoptosis of germ cells. Merideth et al. (2019) evaluated 60 women with xeroderma pigmentosum and found that 31% of these patients had experienced menopause, with 78% meeting criteria for premature menopause; the median age at menopause was 29.5 years, approximately 20 years earlier than in the general population. Conclusions Awareness of the increased risk of premature menopause in women with xeroderma pigmentosum warrants early surveillance to detect declining ovarian reserve and to guide reproductive management. When indicated, initiation of hormone replacement therapy is essential to prevent skeletal and cardiovascular complications.
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.
2026-06-16 | 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.
proteins
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.
2026-04-11 | Clinicopathological and molecular characterization of tumor-associated macrophages in sporadic and Xeroderma Pigmentosum-related cutaneous melanoma.
BACKGROUND: Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder, resulting from genetic defects in the nucleotide excision repair (NER) pathway. It predisposes individuals to skin cancers, including melanoma. The melanoma microenvironment is enriched with inflammatory mediators, particularly macrophages, which may serve as prognostic biomarkers or therapeutic targets. While inflammation is linked to melanoma outcomes, its role in carcinogenesis among XP patients remains poorly understood. METHODS: We assessed the cytokine profiles in the sera of XP-melanoma patients, as well as the expression level of a pan-macrophage marker (CD68), M2-markers CD163, and M1-associated nitric oxide synthase (iNOS) expression. RESULTS: XP patients exhibited significantly reduced levels of iNOS, MIP-1β, MCP-1, and IL-33, indicating an impaired inflammatory and macrophage-mediated immune response. We also found that IL-33 and iNOS levels were positively correlated with the density of inflammatory infiltrates. Moreover, in vitro assays using G361 melanoma cells demonstrated that both pro-inflammatory macrophage-conditioned media and exogenous IL-33 suppressed tumor cell proliferation. CONCLUSION: This study emphasizes the need for specific macrophage biomarkers and proposes local interleukin-33 delivery as a potential therapy for poorly infiltrated melanoma. This also suggests that NER-deficient patients may exhibit unique molecular profiles, warranting personalized treatment.
2025-01-08 | Beyond Nucleotide Excision Repair: The Importance of XPF in Base Excision Repair and Its Impact on Cancer, Inflammation, and Aging.
DNA repair involves various intricate pathways that work together to maintain genome integrity. XPF (ERCC4) is a structural endonuclease that forms a heterodimer with ERCC1 that is critical in both single-strand break repair (SSBR) and double-strand break repair (DSBR). Although the mechanistic function of ERCC1/XPF has been established in nucleotide excision repair (NER), its role in long-patch base excision repair (BER) has recently been discovered through the 5'-Gap pathway. This study briefly explores the roles of XPF in different pathways to emphasize the importance of XPF in DNA repair. XPF deficiency manifests in various diseases, including cancer, neurodegeneration, and aging-related disorders; it is also associated with conditions such as Xeroderma pigmentosum and fertility issues. By examining the molecular mechanisms and pathological consequences linked to XPF dysfunction, this study aims to elucidate the crucial role of XPF in genomic stability as a repair protein in BER and provide perspectives regarding its potential as a therapeutic target in related diseases.
2024-03-25 | Generation of site-specifically labelled fluorescent human XPA to investigate DNA binding dynamics during nucleotide excision repair.
Nucleotide excision repair (NER) promotes genomic integrity by removing bulky DNA adducts introduced by external factors such as ultraviolet light. Defects in NER enzymes are associated with pathological conditions such as Xeroderma Pigmentosum, trichothiodystrophy, and Cockayne syndrome. A critical step in NER is the binding of the Xeroderma Pigmentosum group A protein (XPA) to the ss/ds DNA junction. To better capture the dynamics of XPA interactions with DNA during NER we have utilized the fluorescence enhancement through non-canonical amino acids (FEncAA) approach. 4-azido-L-phenylalanine (4AZP or pAzF) was incorporated at Arg-158 in human XPA and conjugated to Cy3 using strain-promoted azide-alkyne cycloaddition. The resulting fluorescent XPA protein (XPACy3) shows no loss in DNA binding activity and generates a robust change in fluorescence upon binding to DNA. Here we describe methods to generate XPACy3 and detail in vitro experimental conditions required to stably maintain the protein during biochemical and biophysical studies.
2023-03-16 | DNA repair in cardiomyocytes is critical for maintaining cardiac function in mice.
Heart failure has reached epidemic proportions in a progressively ageing population. The molecular mechanisms underlying heart failure remain elusive, but evidence indicates that DNA damage is enhanced in failing hearts. Here, we tested the hypothesis that endogenous DNA repair in cardiomyocytes is critical for maintaining normal cardiac function, so that perturbed repair of spontaneous DNA damage drives early onset of heart failure. To increase the burden of spontaneous DNA damage, we knocked out the DNA repair endonucleases xeroderma pigmentosum complementation group G (XPG) and excision repair cross-complementation group 1 (ERCC1), either systemically or cardiomyocyte-restricted, and studied the effects on cardiac function and structure. Loss of DNA repair permitted normal heart development but subsequently caused progressive deterioration of cardiac function, resulting in overt congestive heart failure and premature death within 6 months. Cardiac biopsies revealed increased oxidative stress associated with increased fibrosis and apoptosis. Moreover, gene set enrichment analysis showed enrichment of pathways associated with impaired DNA repair and apoptosis, and identified TP53 as one of the top active upstream transcription regulators. In support of the observed cardiac phenotype in mutant mice, several genetic variants in the ERCC1 and XPG gene in human GWAS data were found to be associated with cardiac remodelling and dysfunction. In conclusion, unrepaired spontaneous DNA damage in differentiated cardiomyocytes drives early onset of cardiac failure. These observations implicate DNA damage as a potential novel therapeutic target and highlight systemic and cardiomyocyte-restricted DNA repair-deficient mouse mutants as bona fide models of heart failure.
gene therapies
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 ].
2026-06-01 | HX08 From ‘children who burn in sunlight’ to DNA repair defect: xeroderma pigmentosum and the birth of molecular dermatology
Abstract In the late nineteenth century, Hebra and Kaposi described children whose skin developed severe pigmentation, scarring and ulceration after minimal exposure to sunlight. These patients frequently developed multiple skin cancers in early childhood and often died young. The condition, later termed xeroderma pigmentosum (XP), was clinically recognizable but biologically unexplained. For much of the early 20th century, XP was managed as an extreme photosensitivity disorder. Treatment consisted almost entirely of avoidance: strict sun protection, protective clothing and social isolation. Care focused on shielding patients from injury rather than understanding the mechanism. As later commentators noted, management relied on environmental restriction rather than biological explanation. A fundamental shift occurred in 1968, when Cleaver demonstrated that cells from patients with XP were unable to repair ultraviolet-induced DNA damage. This discovery established XP as the first human disease directly linked to a defect in DNA repair. The skin was no longer viewed as unusually sensitive; it was genetically incapable of correcting environmental injury. With this finding, dermatology entered the molecular era. The implications extended far beyond a rare genodermatosis. XP provided direct evidence that cancer could result from failure of genomic maintenance. DNA repair disorders became models for carcinogenesis, revealing a fundamental principle of cancer biology. This insight transformed care. Modern management of XP includes early genetic diagnosis, rigorous cancer surveillance, chemoprevention and multidisciplinary support. Patients are no longer defined by isolation, but by proactive protection and counselling. The history XP illustrates dermatology’s unique contribution to molecular medicine. A rare childhood condition reframed ultraviolet radiation as a mutagen and the skin as a site of genomic vulnerability. XP demonstrates how careful attention to cutaneous disease can uncover mechanisms that reshape all of medicine, marking one of dermatology’s clearest transitions from descriptive specialty to molecular science.
2026-03-01 | 301P Early access program of birabresib in NUT carcinoma patients
Background: Rare malignancies arising in genetic cancer syndromes, chronic inflammatory states, congenital anomalies, therapy-related settings, and those with unusual paraneoplastic or metastatic patterns represent a distinct, under-reported subgroup Here we are presenting 37 such rare malignancies due to the rarity and for documentation.Methods: This retrospective observational study included 37 patients treated between January 1998 and August 2025 at a tertiary cancer center in Eastern India.Eighteen cases had been previously published and 19 new cases were added.Patients were categorized into: (1) common malignancies arising in rare genetic or acquired predisposing conditions, and (2) common malignancies with rare clinical, biological, paraneoplastic, or metastatic manifestations.Results: Patients with xeroderma pigmentosum (n=6) had squamous, basal cell and malignant melanomas with tongue and ovarian carcinoma, Tuberous sclerosis (n=4) had SEGA and bilateral renal angiomyolipomas.Neurofibromatosis (n=7) had malignant peripheral nerve sheath tumors and intracranial tumors, hereditary multiple exostoses (n=1) had chondrosarcomaa nd Klinefelter syndrome (n=1) had CML.Malignancies arising in chronic states were SCC over burn scars (n=3), filarial scrotum (n=1), tropical ulcer (n=1), adenocarcinoma in ectopia vesicae (n=1).Therapy-related second cancer were meningioma 12 years after childhood ALL and AML 63 months after CTRT for cancer cervix. 2 patients had primary granulocytic sarcoma of meninges and mediastinum.Paraneoplastic syndromes included carcinoma larynx with pemphigus, bronchial carcinoid with ectopic cushing's syndrome and solitary fibrous tumor with hypoglycemia.Rare associations included vanishing bone disease, ectopic male breast cancer on the upper chest wall, synchronous GIST with papillary RCC, synchronous Lobular carcinoma of breast with clear cell carcinoma of right kidney and colonic metastasis from IDC of the breast.Conclusions: Due to the rarity lifelong surveillance, early genetic counseling, prompt evaluation of chronic non-healing lesions, and structured survivorship follow-up are essential to improve outcomes in high-risk populations.
2026-02-06 | [Clinical characterization and genetic analysis of a patient with Xeroderma pigmentosum in conjunct with basal cell carcinoma and melanoma due to variants of XPC gene].
To explore the clinical presentation and genetic etiology of a case with Xeroderma pigmentosum in conjunct with basal cell carcinoma and melanoma. A male patient with Xeroderma pigmentosum treated at Xinxiang Central Hospital in October 2022 was selected as study subject. Whole exome sequencing (WES) was carried out. Candidate variants were verified by Sanger sequencing of his family members. This study was approved by the Ethics Committee of the hospital (Ethics No.: 2021-167). Magnetic resonance imaging showed that the patient has a solid soft tissue mass in the anterior and lower part of his right eyeball and a small nodule on the left nasal wing. Histopathological biopsy showed that the periocular tumor was basal cell carcinoma in conjunct with malignant melanoma, and the nasal wing tumor was basal cell carcinoma. WES and Sanger sequencing revealed that he has harbored compound heterozygous variants of the XPC gene, namely c.2391delT (p.F797Lfs*11) and IVS1+1G>A, which were inherited from his father and mother, respectively. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variants were rated as likely pathogenic (PVS1+PM2_Supporting+PM3) and pathogenic (PVS1+PM2_Supporting+PM3+PP5), respectively. The c.2391delT variant was unreported previously. Bioinformatic analysis suggests that it could significantly affect the tertiary structure of XPC protein. The c.2391delT(p.F797Lfs*11) and IVS1+1G>A compound heterozygous variants probably underlay the pathogenesis in this patient. The detection of the novel variant has enriched the mutational spectrum of the XPC gene.
2026-02-04 | Arabidopsis XPD functions upstream of CDKA;1 to regulate stomatal development.
In eukaryotes, XERODERMA PIGMENTOSUM GROUP D (XPD) is an integral subunit of the DNA repair/transcription complex TFIIH. In animals, XPD has been implicated in TFIIH-independent complexes regulating cell division, which, however, remains poorly understood in plants. Here, we identified XPD as a novel regulator of stomatal development in Arabidopsis. Its loss-of-function mutants exhibited increased stomatal precursor cells and formed stomatal clusters. Genetic analysis showed that XPD functions upstream of SPEECHLESS (SPCH) to control stomatal lineage entry, coordinates with MUTE to regulate meristemoid division and works together with FLP and FAMA to restrict GMC division. In a search of XPD interactors, we identified CDKA;1, which serves as both an essential cyclin-dependent kinase and a key SPCH activator. Consistently, xpd mutants exhibited enhanced stomatal lineage cell divisions and elevated SPCH protein levels. Furthermore, XPD acts upstream of CDKA;1, as expression of the dominant-negative CDKA;1.N146 allele significantly suppressed the excessive cell division and stomatal development defects in xpd plants. Our data highlight the precise regulation of stomatal development by XPD, expanding its critical TFIIH-independent roles in plant cell division and fate specification.
oligonucleotides
2025-11-17 | Expanding the landscape of nucleotide excision repair disorders: from discovery to therapy.
DNA damage and repair are central to the onset of cancer, aging, and aging-related diseases. Rare genetic defects in the nucleotide excision repair pathway, such as those causing the cancer-prone disorder xeroderma pigmentosum (XP) or the progeroid condition Cockayne syndrome, highlight the dramatic consequences of unrepaired DNA lesions. In this issue of the JCI, two related papers from Ogi and coworkers - Fassihi et al. and Nakazawa et al. - describe a new XP clinical entity, XP-J, linked to a pathogenic variant in the p52 subunit of the transcription-repair complex TFIIH. The studies' characterization of XP-J and the p52ΔC variant opened unexpected possibilities to ameliorate the molecular defect in another subunit of TFIIH that causes a different, more severe repair syndrome: trichothiodystrophy. This commentary provides a broader historical, medical, and molecular context for the intricate genotype-phenotype relationship between compromised repair and its clinical consequences and discusses next steps for the advances reported.
2025-09-09 | TFIIH-p52ΔC defines a ninth xeroderma pigmentosum complementation-group XP-J and restores TFIIH stability to p8-defective trichothiodystrophy.
Few drugs are available for rare diseases due to economic disincentives. However, tailored medications for extremely rare disorders (N-of-1) offer a ray of hope. Artificial antisense oligonucleotides (ASOs) are now best known for their use in spinal muscular atrophy (SMA). The success of nusinersen/Spinraza for SMA indicates the potential of ASO therapies for other rare conditions. We propose a strategy to develop N-of-1 ASOs for treating one form of trichothiodystrophy (TTD), a rare condition with multisystem abnormalities and reduced life expectancy, associated with instability and greatly reduced amounts of the DNA-repair/transcription factor TFIIH. The therapeutic targets carry mutations in GTF2H5, encoding the TFIIH-p8 subunit. This approach was inspired by the diagnosis and molecular dissection of a xeroderma pigmentosum (XP) case with mutations in GTF2H4, encoding the TFIIH-p52 subunit. This is newly classified as a ninth XP complementation-group, XP-J, identified 5 decades after the discovery of the other XP complementation-groups. The p8-p52 interaction is required to support the TFIIH-complex formation, and the patient's p52 C-terminal truncation results in the complete absence of p8 in TFIIH. However, intriguingly, TFIIH remained stable in vivo, and the patient with XP-J did not exhibit any TTD-features. The aim of our ASO-design is to induce a C-terminal truncation of p52 and we have successfully stabilized TFIIH in p8-deficient cells from patients with TTD-A.
2023-06-28 | Deep intronic founder mutations identified in the ERCC4/XPF gene are potential therapeutic targets for a high-frequency form of xeroderma pigmentosum.
Xeroderma pigmentosum (XP) is a genodermatosis defined by cutaneous photosensitivity with an increased risk of skin tumors because of DNA repair deficiency. The worldwide prevalence of XP is ~1 to 4 in million, with higher incidence in some countries and regions including Japan (1 in 22,000) and North Africa due to founder mutations and a high degree of consanguinity. Among XP, the complementation group F (XP-F), is a rare form (1% of worldwide XP); however, this is underdiagnosed, because the ERCC4/XPF gene is essential for fetal development and most of previously reported ERCC4/XPF pathogenic variants are hypomorphs causing relatively mild phenotypes. From the largest Japanese XP cohort study, we report 17 XP-F cases bearing two pathogenic variants, both identified in deep intronic regions of the ERCC4/XPF gene. The first variant, located in intron 1, is a Japanese founder mutation, which additionally accounts for ~10% of the entire Japanese XP cases (MAF = 0.00196), causing an aberrant pre-mRNA splicing due to a miss-binding of U1snRNA. The second mutation located in intron eight induces an alternative polyadenylation. Both mutations cause a reduction of the ERCC4/XPF gene expression, resulting in XP clinical manifestations. Most cases developed early-onset skin cancers, indicating that these variants need critical attention. We further demonstrate that antisense oligonucleotides designed for the mutations can restore the XPF protein expression and DNA repair capacity in the patients' cells. Collectively, these pathogenic variants can be potential therapeutic targets for XP.
2019-06-21 | Nucleotide excision repair of abasic DNA lesions
Apurinic/apyrimidinic (AP) sites are a class of highly mutagenic and toxic DNA lesions arising in the genome from a number of exogenous and endogenous sources. Repair of AP lesions takes place predominantly by the base excision pathway (BER). However, among chemically heterogeneous AP lesions formed in DNA, some are resistant to the endonuclease APE1 and thus refractory to BER. Here, we employed two types of reporter constructs accommodating synthetic APE1-resistant AP lesions to investigate the auxiliary repair mechanisms in human cells. By combined analyses of recovery of the transcription rate and suppression of transcriptional mutagenesis at specifically positioned AP lesions, we demonstrate that nucleotide excision repair pathway (NER) efficiently removes BER-resistant AP lesions and significantly enhances the repair of APE1-sensitive ones. Our results further indicate that core NER components XPA and XPF are equally required and that both global genome (GG-NER) and transcription coupled (TC-NER) subpathways contribute to the repair.
2010-03-01 | Targeting and processing of site‐specific DNA interstrand crosslinks
Abstract DNA interstrand crosslinks (ICLs) are among the most cytotoxic types of DNA damage, and thus ICL‐inducing agents such as cyclophosphamide, melphalan, cisplatin, psoralen, and mitomycin C have been used clinically as anticancer drugs for decades. ICLs can also be formed endogenously as a consequence of cellular metabolic processes. ICL‐inducing agents continue to be among the most effective chemotherapeutic treatments for many cancers; however, treatment with these agents can lead to secondary malignancies, in part due to mutagenic processing of the DNA lesions. The mechanisms of ICL repair have been characterized more thoroughly in bacteria and yeast than in mammalian cells. Thus, a better understanding of the molecular mechanisms of ICL processing offers the potential to improve the efficacy of these drugs in cancer therapy. In mammalian cells, it is thought that ICLs are repaired by the coordination of proteins from several pathways, including nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR), homologous recombination (HR), translesion synthesis (TLS), and proteins involved in Fanconi anemia (FA). In this review, we focus on the potential functions of NER, MMR, and HR proteins in the repair of and response to ICLs in human cells and in mice. We will also discuss a unique approach, using psoralen covalently linked to triplex‐forming oligonucleotides to direct ICLs to specific sites in the mammalian genome. Environ. Mol. Mutagen. 2010. © 2010 Wiley‐Liss, Inc.
other
2026-08-27 | Clinics, Genetics and Treatment in a Russian Cohort of Young Patients with Xeroderma Pigmentosum: A Single Center Experience
Xeroderma pigmentosum (XP) and Cockayne syndrome (CS) are rare autosomal recessive DNA repair disorders. XP is characterized by extreme sensitivity to UV-radiation and a very high risk of skin cancer. To date, little is known about the clinical characteristics and genetic basis of these diseases in Russia. Here, we present a detailed study of 14 patients (aged 5–30 years) from 11 unrelated families of diverse ethnic backgrounds. Using a multigene panel or whole-genome sequencing, we identified homozygous or compound heterozygous variants in XPC (8 patients) and XPA (3 patients). In one family with two XP cases, a patient with CS and compound heterozygous ERCC6 variants was identified. In total, 110 family members were screened to determine their carrier status. Skin cancer was revealed in 12/13 (92%) of XP patients, with a median age at diagnosis of 12.5 years (range 5–22). Basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma developed in 10, 6, and 3 patients, respectively. All three cancer types occurred in 2 patients. All patients underwent surgical treatment; additionally, two patients with BCC received targeted therapy (vismodegib, sonidegib). Anti-PD-1 immunotherapy was administered with a favorable clinical response in three patients with advanced SCC or melanoma.
2026-05-23 | Synergistic enhancement of PD-L1 expression from DNA repair dysfunction and UV exposure in xeroderma pigmentosum: Potential therapeutic role of PD-L1 inhibitors.
Xeroderma pigmentosum (XP) is a rare genetic disorder caused by defective nucleotide excision repair, leading to extreme UV sensitivity and early-onset skin cancers. Although PD-1/PD-L1 inhibitors have shown benefit in XP-associated tumors, the mechanisms that underpins these therapeutic responses remains unclear. To elucidate the molecular basis of XP pathogenesis in a 4-year-old Filipino girl and to investigate the potential role of PD-L1 inhibitors in treating XP-associated squamous cell carcinoma (SCC). A 4-year-old girl with XP underwent germline whole-exome sequencing. Transcriptomic profiling and immunochemistry validation were performed on XP-SCC and non-XP SCC tissues. In vitro assays using HaCaT keratinocytes evaluated DNA damage and PD-L1 expression following XPA knockdown and UV radiation. A Jurkat-HaCaT co-culture system, incorporating a PD-L1 neutralizing antibody, assessed T-cell attachment. A homozygous splice-site variant in XPA (c.556-1 C>G) was identified. RNA-seq revealed marked up-regulation of CD274 (PD-L1), PDCD1 (PD-1), and STAT1 in XP-SCC. In vitro, XPA-deficient keratinocytes exhibited increased UV-induced DNA damage and synergistic PD-L1 induction. Jurkat T-cell attachment was elevated in UV-exposed, XPA-deficient groups; crucially, this enhanced attachment was significantly abolished by PD-L1 blockade. XPA deficiency and UV-induced stress jointly enhance PD-L1 expression in XP-associated cSCC. These molecular and functional data provide biologic rationale for PD-L1-targeted therapy in XP and support further evaluation of immune checkpoint inhibitors in this population.
2026-04-23 | Efficacy of immune checkpoint inhibitors in patients with xeroderma pigmentosum and advanced cutaneous squamous-cell carcinoma and literature review.
Xeroderma pigmentosum (XP) is a disorder characterized by defective DNA repair, leading to the early development of cutaneous malignancies, including cutaneous squamous cell carcinomas (cSCC). The management of locally advanced and metastatic cSCC in XP patients is particularly challenging, primarily due to the risk of major surgical sequelae and the hazardous use of radiotherapy. This study aims to evaluate the efficacy and safety of anti-PD1 immunotherapy in XP patients with unresectable cSCC in Mayotte and Réunion Island and to conduct a literature review. This retrospective multicenter study included XP patients treated with anti-PD1 for advanced or metastatic inoperable cSCC between June 2023 and February 2025. The efficacy and safety of the treatment were assessed based on clinical, biological, and radiological data from patient records. A literature review of similar cases was also conducted. Four XP patients, with a median age of 16 years, were treated with immunotherapy for cSCC or sarcomatoid carcinoma, achieving rapid and complete tumour regression in all cases. No major adverse effects were reported. The literature review identified 14 additional cases, including 7 complete responses and 6 partial responses. Anti-PD1 therapy is effective in XP patients with advanced cSCC, offering a therapeutic alternative to surgery. These findings raise the question of earlier neoadjuvant initiation to reduce the risk of major surgical sequelae or prevent metastatic progression.
2026-04-08 | Long‐Term Clinical Response After Low‐Dose and Short‐Duration Cemiplimab Therapy in a Patient With Xeroderma Pigmentosum in Nepal
ABSTRACT Xeroderma pigmentosum (XP), an autosomal recessive condition affecting DNA repair, is associated with a high risk of multiple and aggressive cutaneous squamous cell carcinomas (CSCCs). Because of numerous and/or locally advanced tumors, surgery may be difficult. The immune checkpoint inhibitor cemiplimab has been approved in advanced, unresectable, and/or metastatic CSCCs. However, it is not available everywhere and is typically inaccessible to the poor without health insurance. We hereby report our experience of using low‐dose and short‐duration treatment with cemiplimab in a 15‐year‐old male with XP and multiple advanced CSCCs. The patient showed a complete or partial response to all tumors. The therapy was subsequently stopped after eight pulses due to the COVID‐19 pandemic. The response lasted for 5 years without subsequent treatment, after which one of the tumors recurred and the new ones developed. Checkpoint inhibitors were no longer available at this time.
2026-01-21 | Pembrolizumab therapy leads to resolution of lentigines and tumour control in a patient with xeroderma pigmentosum and advanced cutaneous squamous cell carcinoma
We describe a 54-year-old patient with xeroderma pigmentosum (XP) who developed unresectable cutaneous squamous cell carcinoma and was treated with pembrolizumab, an immune checkpoint inhibitor (ICI). The treatment led to significant tumour regression and, unexpectedly, a complete resolution of the patient’s lentigines, while vitiligo and other pigmented lesions remained unchanged. The findings suggest that ICIs may amplify immune responses against ultraviolet-induced pigmented lesions in patients with XP, potentially linked to the disease’s high mutational burden. Further studies are needed to elucidate the underlying mechanisms.
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 | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Afamelanotide | peptides | EMA | Clinuvel Europe Limited | |
Pro-Pro-Thr-Val-Pro-Thr-Arg | peptides | FDA | — | ProGeLife S.A.S |
PRO-PRO-THR-VAL-PRO-THR-ARG [INHOX] | peptides | EMA | — | ProGeLife S.A.S. |
T4 endonuclease V, liposome encapsulated | proteins | FDA | — | AGI Dermatics |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.