RARE DISEASE
Werner syndrome
Werner syndrome
Werner syndrome
Synonyms: Adult progeria, WS
Synonyms: Adult progeria, WS
Synonyms: Adult progeria, WS
Drug discovery
1
drug
With orphan designation
Overview
Werner syndrome (WS) is a rare autosomal recessive disorder caused by WRN gene mutations, leading to defective DNA repair and premature aging. Key features include short stature, bilateral cataracts, greying hair, scleroderma-like skin changes, and early-onset age-related conditions (type 2 diabetes, atherosclerosis, osteoporosis). Patients face elevated cancer risks (sarcomas, melanomas) and typically experience life-threatening complications by their 40s–50s, primarily from malignancies or cardiovascular events [1][2][6][12].
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare neoplastic diseases, rare ophthalmic disorders, rare skin diseases
Research Papers
455 drug discovery papers about Werner syndrome, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
455 drug discovery papers about Werner syndrome, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2025-12-08 | Tumorigenic p53N236S balances aging and tumorigenesis via regulating DREAM/MMB and downstream telomere DNA replication pathways.
The Werner syndrome (WS) is characterized with both premature aging and tumorigenic phenotypes. In this study, we introduced a tumorigenic mutation p53N236S (referred to as p53S later), which is found in immortalized WS mouse embryo fibroblasts, back into WS mice to investigate its impact on the telomere dysfunction-induced aging process. Intriguingly, the introduction of p53S rescued the aging phenotypes of WS mice, showing the extension of the lifespan and the delay in organ degeneration. Further studies revealed that the introduction of p53S transcriptionally upregulated the DREAM/MMB pathway and downstream DNA helicases and telomere maintenance proteins, facilitated the recruitment of these proteins to G-quadruplex (G4) DNA structures proximal to DNA replication forks, and promoted the unwinding of G4. By comparing the cellular responses to pyridostatin and hydroxyurea, respectively, we confirmed that p53S specifically regulates G4-related DNA replication stress. Thus, p53S compensates the loss of Wrn and telomerase function, solves the DNA replication, telomere lengthening, and cell proliferation problems in WS cells, and ultimately rescues the aging phenotypes of WS. Together, our data indicate that certain tumorigenic features can be applied to balance with premature aging, rescuing the aging phenotype without tumorigenic risk. This study suggests a new mechanism in aging regulation and provides the possibility of developing a tumor-free longevity strategy and targeting G4 and DNA replication in aging-related tumor therapy.
2025-01-15 | Synergistic protection of nascent DNA at stalled forks by MSANTD4 and BRCA1/2-RAD51.
The regressed arms of reversed replication forks exhibit structural similarities to one-ended double-stranded breaks and need to be protected against uncontrolled nucleolytic degradation. Here, we identify MSANTD4 (Myb/SANT-like DNA-binding domain-containing protein 4), a functionally uncharacterized protein that uniquely counters the replication protein A (RPA)-Bloom (BLM)/Werner syndrome helicase (WRN)-DNA replication helicase/nuclease 2 (DNA2) complex to safeguard reversed replication forks from detrimental degradation, independently of the breast cancer susceptibility proteins (BRCA1/2)-DNA repair protein RAD51 pathway. MSANTD4 specifically interacts with the junctions between single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) in DNA substrates harboring a 3' overhang, which resemble the structural features of regressed arms processed by WRN-DNA2. This DNA-binding capability allows MSANTD4 to accumulate at reversed forks, strategically antagonizing the RPA-BLM/WRN-DNA2 complex by impeding its access to the ssDNA-dsDNA junction of the regressed arms. Loss of MSANTD4 exacerbates genome instability induced by replication stress in BRCA1/2-deficient cells. Our findings unveil a collaborative defense mechanism orchestrated by MSANTD4 and BRCA1/2-RAD51, effectively counteracting nucleolytic attacks on the regressed arms and synergistically preserving the integrity of reversed forks.
2024-09-29 | p21 Regulates Wnt-Notch balance via DREAM/MMB/Rb-E2F1 and maintains intestinal stem cell homeostasis.
The crosstalk and balance regulation of Wnt-Notch have been known to be essential for cell fate decision and tissue regeneration, however, how this balance is maintained and how the Wnt-Notch pathways are connected with cell cycle regulation is still not clear. By analyzing the molecular alterations in mouse model with accelerated aging phenotypes due to loss of p21 function in a Werner syndrome background, we observed that Wnt3 and β-Catenin were down-regulated, while Notch1 and Hes1 were up-regulated. This disruption in Wnt-Notch signaling was accompanied by the loss of intestinal stem cell compartment, increase in Bmi1 positive cells, loss of Olfm4/Lgr5 positive cells, and reduced secretory Paneth cells and goblet cells in the intestinal crypts of p21TKO mice. BrdU incorporation, cleaved caspase 3, and Tunel assay results revealed the fast turnover of intestinal epithelia, which may result in abnormal stem cell mobilization and exhaustion of the stem cell reservoir in the intestinal crypts. We further identified shift of DREAM complex towards MMB complex due to the loss of p21 as the cause for faster turnover of intestinal epithelia. Importantly, we identified the E2F1 as the transcriptional regulator for Notch1, which linked the p21-DREAM/MMB/Rb-E2F1 pathway with Wnt-Notch pathway. The overexpression of p21 rescued the DREAM pathway, as well as the imbalance of Wnt-Notch pathway. In summary, our data identify p21 as an important factor in maintaining sequential mobilization, proliferation, and homeostasis of intestinal stem cells.
2024-01-12 | O-09 A rare cause of acute pancreatitis: Werner Syndrome
Abstract Introduction Lipodystrophies are rare disorders characterized by loss of body fat resulting in leptin deficiency. Patients are predisposed to metabolic complications such as severe insulin resistance, hypertriglyceridemia, and hepatic steatosis. Werner syndrome (WS) is among the progeroid syndromes in the classification of lipodystrophy. Due to its extremely rare occurrence, it can often be overlooked by the clinician. Clinical Case A 19 years old male patient hospitalized for non-biliary acute pancreatitis was consulted for hypertriglyceridemia and hyperglycemia. He had no history of any disease or medication use. His sister was diagnosed with type 2 diabetes mellitus at age 29. She was using linagliptin and gliclazide for 3 years. She had short stature (147 cm) and low body weight (40 kg) and had scleroderma-like skin findings. The patient also had short stature (157 cm) and low body weight (41 kg). He had scleroderma-like skin findings and generalized loss of subcutaneous adipose tissue. The laboratory results were; glucose, 261 mg/dl; creatinine, 0.46 mg/dl; ALT, 24 U/l; lipase, 161 U/l; HbA1c, 9.6%; triglyceride, 799 mg/dl; HDL, 9.6 mg/dl; LDL, 75 mg/dl; c-peptide, 4.3 ng/dl. The thyroid function test results (TSH: 29.7 µIU/ml, fT4: 6.81 pmol/L, Anti-TPO: negative) were consistent with primary hypothyroidism. Hepatosteatosis was observed in abdominal ultrasonography. We initiated intensive insulin, metformin as well as fenofibrate and levothyroxine treatment. The patient needed high insulin doses (60 IU/day). Measured serum leptin levels were found to be low (2.11 ng/ml) in suspicion of lipodystrophy. Genetic analysis of the patient and his sister showed homozygous mutation in the WRN gene (c.1105C>T p.Arg369Ter, Homozygous) which was compatible with WS. The patient was started on leptin analog therapy in a clinical trial. Conclusion WS is an exceptionally rare autosomal recessive genetic disorder characterized by premature aging and multisystemic complications. The clinical features encompass scleroderma-like skin changes, short stature, low body weight, alopecia, cataracts, osteoporosis, and a propensity for atherosclerotic complications and malignancies. Impaired glucose tolerance is reported in 15%–20% of WS subjects, diabetes mellitus in 55%–70%, and dyslipidemia in 60%–85%. The presence of hypertriglyceridemia, diabetes mellıtus and generalized lack of subcutaneous adipose tissue led us to suspect from lipodystrophy. Although acute pancreatitis due to hypertriglyceridemia can be seen in lipodystrophy (15-20%), first presentation of WS presenting with acute pancreatitis is very rare in the literature. The most common mutation in non-Japanese patients in WRN gene is c.1105 C>T (18.6%). Metreleptin, an analog of human leptin, is shown to ameliorate the metabolic derangements. WS remains a diagnostic challenge due to its rarity, atypical presentation, and should be kept in mind in patients with severe dyslipidemia and insulin resistance.
2023-12-28 | Cellular Reprogramming, Transdifferentiation and Alleviation of the Aging Pathology
Cellular reprogramming and transdifferentiation have emerged as transformative technologies in regenerative medicine, holding significant promise for addressing age-related pathologies and rare genetic disorders. Dr. Shinya Yamanaka's pioneering work in cellular reprogramming paved the way for the restoration of pluripotency in terminally differentiated cells. The understanding that exogenous introduction of the key transcription factors (Oct4, Sox2, KLF4 and c-Myc) enables cells for reprogramming, regaining pluripotency has provided tremendous opportunities and better platforms for therapeutic implications. Transdifferentiation, the conversion of one differentiated cell type to another, offers a complementary approach to cellular reprogramming and can be procured by modulating the expression of specific transcription factors, miRNAs, or other small molecules. Therapeutic approaches that utilize transdifferentiated cells are promising in addressing the age-related pathologies of vital organs such as the pancreas, liver, cardiovascular system as well as neurological disorders. Additionally, the emerging field of epigenetic rejuvenation offers extended possibilities for targeted interventions as it focuses on targeting age-associated CpG signatures of the epigenome. Induced pluripotent stem cells (iPSCs) obtained by cellular reprogramming have become invaluable tools for studying rare monogenic syndromes and premature aging diseases that include Hutchinson-Gilford Progeria Syndrome (HGPS) and Werner syndrome. iPSCs enable researchers to model diseases and gain insights into their underlying mechanisms. Translation of these technologies into clinical practice just needs bypassing hurdles related to safe, efficient, specific therapeutic outcomes. Thus, recent advancements in stem cell technologies highlight that cellular reprogramming and transdifferentiation are poised to revolutionize healthcare, providing novel approaches to address age-related pathologies and other genetic disorders.
cell therapies
2024-01-31 | Sex-specific preservation of neuromuscular function and metabolism following systemic transplantation of multipotent adult stem cells in a murine model of progeria.
Onset and rates of sarcopenia, a disease characterized by a loss of muscle mass and function with age, vary greatly between sexes. Currently, no clinical interventions successfully arrest age-related muscle impairments since the decline is frequently multifactorial. Previously, we found that systemic transplantation of our unique adult multipotent muscle-derived stem/progenitor cells (MDSPCs) isolated from young mice-but not old-extends the health-span in DNA damage mouse models of progeria, a disease of accelerated aging. Additionally, induced neovascularization in the muscles and brain-where no transplanted cells were detected-strongly suggests a systemic therapeutic mechanism, possibly activated through circulating secreted factors. Herein, we used ZMPSTE24-deficient mice, a lamin A defect progeria model, to investigate the ability of young MDSPCs to preserve neuromuscular tissue structure and function. We show that progeroid ZMPST24-deficient mice faithfully exhibit sarcopenia and age-related metabolic dysfunction. However, systemic transplantation of young MDSPCs into ZMPSTE24-deficient progeroid mice sustained healthy function and histopathology of muscular tissues throughout their 6-month life span in a sex-specific manner. Indeed, female-but not male-mice systemically transplanted with young MDSPCs demonstrated significant preservation of muscle endurance, muscle fiber size, mitochondrial respirometry, and neuromuscular junction morphometrics. These novel findings strongly suggest that young MDSPCs modulate the systemic environment of aged animals by secreted rejuvenating factors to maintain a healthy homeostasis in a sex-specific manner and that the female muscle microenvironment remains responsive to exogenous regenerative cues in older age. This work highlights the age- and sex-related differences in neuromuscular tissue degeneration and the future prospect of preserving health in older adults with systemic regenerative treatments.
2022-10-28 | Research on Werner Syndrome: Trends from Past to Present and Future Prospects.
A rare and autosomal recessive premature aging disorder, Werner syndrome (WS) is characterized by the early onset of aging-associated diseases, including shortening stature, alopecia, bilateral cataracts, skin ulcers, diabetes, osteoporosis, arteriosclerosis, and chromosomal instability, as well as cancer predisposition. WRN, the gene responsible for WS, encodes DNA helicase with a 3' to 5' exonuclease activity, and numerous studies have revealed that WRN helicase is involved in the maintenance of chromosome stability through actions in DNA, e.g., DNA replication, repair, recombination, and epigenetic regulation via interaction with DNA repair factors, telomere-binding proteins, histone modification enzymes, and other DNA metabolic factors. However, although these efforts have elucidated the cellular functions of the helicase in cell lines, they have not been linked to the treatment of the disease. Life expectancy has improved for WS patients over the past three decades, and it is hoped that a fundamental treatment for the disease will be developed. Disease-specific induced pluripotent stem (iPS) cells have been established, and these are expected to be used in drug discovery and regenerative medicine for WS patients. In this article, we review trends in research to date and present some perspectives on WS research with regard to the application of pluripotent stem cells. Furthermore, the elucidation of disease mechanisms and drug discovery utilizing the vast amount of scientific data accumulated to date will be discussed.
2021-09-01 | Successful allogeneic stem cell transplantation of a patient with Werner syndrome and acute myeloid leukemia
• Werner syndrome is an adult-onset syndrome of accelerated aging predisposing to solid cancer and hematological malignancies. • Chemotherapy and stem cell transplantation was successful in a patient with Werner syndrome and AML. • Despite the poor risk profile, the patient remains in remission 5 years after transplantation and toxicity was acceptable.
2018-08-23 | Successful Cord Blood Transplantation in a Werner Syndrome Patient with High-risk Myelodysplastic Syndrome
Werner syndrome (WS) confers a high risk of the development of neoplasias, including hematological malignancies, and curative treatment for these malignancies is difficult to achieve. A 44-year-old man with myelodysplastic syndrome was admitted to our hospital. He was diagnosed with mutation-proven WS. He underwent cord blood transplantation (CBT) following fludarabine, busulfan, and melphalan administration. A chimerism analysis of his marrow blood on day 62 showed a donor pattern >95%, which confirmed engraftment. The patient lived for 15 months while maintaining remission of MDS without treatment-related toxicity. Our case shows that CBT can be a treatment modality for WS patients with hematological malignancies.
2015-01-29 | Werner Syndrome-specific induced pluripotent stem cells: recovery of telomere function by reprogramming
Werner syndrome (WS) is a rare human autosomal recessive premature aging disorder characterized by early onset of aging-associated diseases, chromosomal instability, and cancer predisposition. The function of the DNA helicase encoded by WRN, the gene responsible for WS, has been studied extensively. WRN helicase is involved in the maintenance of chromosome integrity through DNA replication, repair, and recombination by interacting with a variety of proteins associated with DNA repair and telomere maintenance. The accelerated aging associated with WS is reportedly caused by telomere dysfunction, and the underlying mechanism of the disease is yet to be elucidated. Although it was reported that the life expectancy for patients with WS has improved over the last two decades, definitive therapy for these patients has not seen much development. Severe symptoms of the disease, such as leg ulcers, cause a significant decline in the quality of life in patients with WS. Therefore, the establishment of new therapeutic strategies for the disease is of utmost importance. Induced pluripotent stem cells (iPSCs) can be established by the introduction of several pluripotency genes, including Oct3/4, Sox2, Klf4, and c-myc into differentiated cells. iPSCs have the potential to differentiate into a variety of cell types that constitute the human body, and possess infinite proliferative capacity. Recent studies have reported the generation of iPSCs from the cells of patients with WS, and they have concluded that reprogramming represses premature senescence phenotypes in these cells. In this review, we summarize the findings of WS patient-specific iPSCs (WS iPSCs) and focus on the roles of telomere and telomerase in the maintenance of these cells. Finally, we discuss the potential use of WS iPSCs for clinical applications.
small molecules
2026-08-13 | Discovery and Optimization of a WRN Helicase Inhibitor Series through Structure-Guided Drug Design from a Covalent Fragment Binding Insight.
WRN helicase activity inhibition has emerged as a promising therapeutic approach for targeting cancer cells with specific DNA repair deficiencies, especially those with microsatellite instability (MSI). Herein, we report a novel covalent WRN helicase inhibitor series discovered and optimized by leveraging insights from a covalent fragment investigation. Initial structure-based design led to potency-optimized compounds from this series that exhibited unbound cellular potency in the nanomolar range in both p21 induction and HCT116 CTG viability assays, albeit with high intrinsic warhead reactivity. Further refinement of the ADME properties by modulating the warhead reactivity yielded lead WC-2 with excellent cellular potency, low reactivity toward GSH, excellent plasma and blood stabilities, good oral bioavailability, and long in vivo half-lives in rat (T1/2 = 7.2 h; F = 62%) and dog (T1/2 = 18.9 h). WC-2 has the potential as a next-generation, low-dose WRN helicase clinical candidate for treating patients with MSI-classified tumors.
2026-08-04 | Data from Microsatellite Instable Cancer Cells Acquire On-target Resistance Mutations to WRN Helicase Inhibitors
<div>Abstract<p>The Werner syndrome helicase (WRN) is a promising target for cancers with microsatellite instability (MSI), leading to the initiation of at least five phase I clinical trials. Acquired resistance is a substantial obstacle to obtaining lasting benefits from targeted therapies in oncology and may be particularly acute in the setting of mismatch repair–deficient (dMMR) tumors, which can sample increased fitness landscapes owing to a higher mutational burden. In this study, we characterized resistance mechanisms using the clinical candidate HRO761 and two novel inhibitors in MSI cell lines and xenograft models. We observed the rapid emergence of resistance both <i>in vitro</i> and <i>in vivo</i>, with sequencing revealing clustered mutations within the <i>WRN</i> helicase domain. Computational structural analyses indicated that these mutations either directly interfere with inhibitor binding or alter the protein conformation required for inhibitor engagement. Notably, although most mutations conferred broad resistance across all three compounds, we identified specific alterations (L528S, C727R, and F730L) that exhibited selectivity between chemical scaffolds. This chemotype-specific resistance profile suggests opportunities for developing next-generation inhibitors that retain activity against resistant variants and for implementing rational treatment strategies with existing inhibitors. Overall, our findings demonstrate that on-target resistance to WRN inhibitors emerges rapidly in dMMR backgrounds but also highlight potential approaches to overcome resistance, supporting the continued development of WRN-targeted therapies for MSI cancers.</p></div>
2026-06-17 | Werner Syndrome: Symptoms, Hallmarks of Aging, Molecular Mechanisms and Therapeutic Pathway Inhibitors
Werner Syndrome (WS) is a rare autosomal recessive progeroid disorder characterized by accelerated aging and the premature onset of age-related conditions, such as stunted growth, cataracts, cardiovascular disease, malignancies, sarcopenia, osteoporosis, and diabetes. Clinical disease manifestations typically begin in adolescence to early adulthood, and result in a reduced lifespan compared to healthy individuals. WS arises from loss-of-function mutations in the WRN gene, which encodes a RecQ family helicase that has implications in DNA repair, replication, and telomere maintenance. Deficiency in functional RecQ helicase activity results in dysfunction that links WS to the hallmarks of aging, including genomic instability, telomere attrition, and premature cellular senescence. To date, there is no cure for WS, with current therapies primarily focusing on disease management through inhibition of important proteins in aging- and stress-related signaling pathways, namely mTOR and p38 MAPK. These emerging approaches have shown promising results in cellular models, but have yet to be tested in human clinical studies. This review therefore examines WS as a potential model for understanding the mechanisms of aging, and the implications of existing findings for informing new therapeutic strategies.
2026-06-12 | Functional orthogonality of WRN inhibitor resistance enables alternating therapy and mutation-tolerant inhibitor design in MSI-H cancers
Abstract Werner syndrome helicase (WRN) is a synthetic-lethal vulnerability in microsatellite instability–high (MSI-H)/mismatch repair–deficient (dMMR) cancers 1–5 , and non-covalent and covalent WRN inhibitors are now entering clinical development 6–9 . A central unresolved question is whether resistance to one WRN inhibitor class inevitably compromises the target, or instead creates actionable vulnerabilities to an alternate modality. Here we generated ten stable acquired-resistance models across three MSI-H cell lines using the non-covalent inhibitor HRO761 and the covalent inhibitor VVD-214. Whole-exome sequencing, biochemical reconstitution and isogenic knock-in models identified recurrent on-target WRN missense mutations as dominant resistance drivers, but with sharply modality-specific spectra: HRO761 resistance clustered at G729/F730/I852, whereas VVD-214 resistance concentrated at E846. These mutations impaired inhibitor engagement and abolished the canonical WRN inhibitor (WRNi)-induced pharmacodynamic cascade, including WRN reduction, DNA damage response (DDR) activation and G 2 /M arrest. Crucially, most resistance mutations retained biochemical, cellular and in vivo sensitivity to the alternate inhibitor modality, revealing a functional orthogonality that enabled a 7-day cyclic alternating regimen to delay tumour regrowth in xenografts. We further identified F730L as an engineered cross-resistant bottleneck model and used structure-guided, artificial intelligence (AI)-enabled optimization to generate GBA-007, a proof-of-concept mutation-tolerant WRN inhibitor candidate with promising activity against F730L in vitro and in vivo. Thus, clinically relevant WRN inhibitor classes impose distinct on-target resistance trajectories that can be exploited through schedule design, while cross-resistant bottlenecks can be addressed by rapid mutation-aware inhibitor engineering.
2026-06-03 | Structure-GuidedDiscovery of Potent, Selective, andOrally Bioavailable Werner Syndrome RecQ Helicase Inhibitors for theTreatment of Microsatellite Instability-High Tumors
Despite recent advances in immunotherapy for microsatellite instability-high (MSI-H) tumors, challenges of resistance persist, necessitating alternative therapeutic approaches. The synthetic lethal interaction between WRN helicase inhibition and MSI status presents a promising therapeutic strategy. Guided by the key structural features of the WRN-HRO761 complex, we rationally designed two classes of WRN inhibitorsspirocyclic compounds and benzo-fused heterocyclic analogsby targeting the solvent-exposed region. Among these, Q15 exhibited potent in vitro activity and excellent cellular selectivity. Compared with HRO761 in vivo, Q15 demonstrated more favorable oral pharmacokinetic properties and superior antitumor efficacy at 10 mg/kg, comparable efficacy at 20 mg/kg, and achieved complete tumor regression at 40 mg/kg. Preliminary safety evaluation further indicated that Q15 possesses a favorable safety profile. These findings support Q15 as a promising WRN inhibitor candidate for the treatment of MSI-H tumors.
gene therapies
2026-06-01 | WRN and Other RecQ Helicases in Life Cycles of Viruses
Abstract RecQ helicases are a conserved family of DNA-unwinding enzymes that play a key role in maintaining genomic stability by participating in DNA damage repair, recombination, replication, and telomere homeostasis. Five RecQ helicases are known in humans: BLM (the Bloom syndrome protein), WRN (Werner syndrome helicase), RECQL4, RECQL1, and RECQL5. All members of the RecQ family possess 3' → 5' helicase activity and are capable of unwinding DNA, including its complex secondary structures, in the 3'-to-5' direction by using the energy of ATP hydrolysis. WRN is unique among RecQ helicases in possessing additional 3' → 5' exonuclease activity, which expands its functionality in maintaining genomic stability. Mutations of the RecQ helicase genes lead to Werner, Bloom, and Rothmund–Thomson syndromes and are associated with a predisposition to cancer and premature aging. The enzymes consequently attract significant interest of the scientific community. Many viruses rely on host cell replication and repair mechanisms for their reproduction, and RecQ helicases may therefore influence the development of viral infections. The review discusses the role of RecQ helicases in replication of various viruses, including socially significant ones, such as the human immunodeficiency virus, herpes simplex virus, Epstein–Barr virus, hepatitis C virus, and others.
2025-08-05 | A case of rapid-progressing liver cirrhosis complicated by Werner syndrome.
Werner syndrome is a rare progeroid condition caused by a mutation in the WRN gene. It is characterized primarily by premature aging, diabetes mellitus, atherosclerosis, and an increased risk of malignancy. In this case, we present a man in his 40s with liver cirrhosis who was subsequently diagnosed with Werner syndrome. Shortly afterwards, he developed refractory ascites and a non-healing ulcer on his left big toe and ultimately died of liver failure. Despite having only mild fatty liver disease and being of normal weight, his liver became cirrhotic within a little over 4 years. Although a liver biopsy was not performed, the presumed etiology of his liver cirrhosis was non-alcoholic fatty liver disease (NAFLD) due to fatty liver disease. This case report highlights the importance of considering Werner syndrome in the differential diagnosis of fatty liver, particularly in the absence of obesity, as it can lead to the rapid progression of NAFLD-related liver cirrhosis.
2025-07-22 | Werner syndrome due to homozygous WRN mutation through chromosome 8 region of homozygosity in a consanguineous family.
An 18-year-old man showing growth retardation, progeroid facies and acral abnormalities was found to have Werner syndrome caused by a homozygous WRN mutation (c.502_503del) located within a 36.7-Mb region of homozygosity on chromosome 8.
2025-04-22 | Underlying data for Fig 5.
Human Werner syndrome (adult progeria, a well-established model of human aging) is caused by mutations in the Werner syndrome (WRN) gene. However, the expression patterns and functions of WRN in natural aging remain poorly understood. Despite the link between WRN deficiencies and progeria, our analyses of human colon tissues, mouse crypts, and Drosophila midguts revealed that WRN expression does not decrease but rather increases in intestinal stem cells (ISCs) with aging. Mechanistically, we found that the Drosophila WRN homologue (WRNexo) binds to Heat shock 70-kDa protein cognate 3 (Hsc70-3/Bip) to regulate the unfolded protein response of the endoplasmic reticulum (UPRER). Activation of the WRNexo-mediated UPRER in ISCs is required for ISC proliferation during injury repair. However, persistent DNA damage during aging leads to chronic upregulation of WRNexo in ISCs, where excessive WRNexo-induced ER stress drives age-associated gut hyperplasia in Drosophila. This study reveals how elevated WRNexo contributes to stem cell aging, providing new insights into organ aging and the pathogenesis of age-related diseases, such as colon cancer.
2025-01-24 | rDNA Copy Number Variation and Methylation During Normal and Premature Aging.
Ribosomal RNA is the main component of the ribosome, which is essential for protein synthesis. The diploid human genome contains several hundred copies of the rDNA transcription unit (TU). Droplet digital PCR and deep bisulfite sequencing were used to determine the absolute copy number (CN) and the methylation status of individual rDNA TU in blood samples of healthy individuals. The absolute CN ranged from 243 to 895 (median 469). There was no difference in absolute CN between males and females and no gain or loss of copies with age (15-71 years). The number of rDNA TU with a completely unmethylated (0%) or lowly methylated (1%-10%) promoter region significantly decreased, whereas the number of copies with higher (11%-100%) methylation increased with age. The number of presumably active TU with a hypomethylated (0%-10%) promoter varied from 94 to 277 (median 180), independent from absolute CN. In contrast, the number of inactive hypermethylated (11%-100%) copies strongly increased with absolute CN. Promoter hypermethylation compensates to some extent for the enormous CN variation among individuals. Patients with Werner syndrome, a premature aging syndrome displayed the same CN variation and age-related methylation changes as controls. The role of rDNA CN variation as a modulating factor in human health and disease is largely unexplored. In particular, very low and high CN may be associated with increased disease risk.
other
2026-08-12 | A skip in time: Frame-restoring exon skipping counters premature aging in Werner syndrome
Antisense oligonucleotide (ASO) technology is a blooming class of therapeutics quickly reaching the fame of gene therapy, offering potential for treating diseases by targeting RNA.1 Worthy of particular interest is the ability of ASOs to modulate splicing, thereby mediating exon skipping. The “skipping to correct a skip” strategy offers the advantage of producing a shorter but still functional protein; this is a clean-cut strategy able to overcome some of those mutations which compromise protein translation and/or functionality.
2026-05-07 | Development of an exon 27-skipping antisense oligonucleotide as a targeted therapy for refractory skin ulcers in Werner syndrome.
Werner syndrome (WS) is a rare autosomal recessive progeroid disorder caused by biallelic mutations in WRN and is frequently complicated by refractory skin ulcers for which no effective therapy exists. We developed WRN-108, a splice-switching antisense oligonucleotide (ASO) designed to induce exon 27 skipping and restore the open reading frame (ORF) disrupted by the most common WRN mutation in Japanese WS patients, c.3139-1G>C, which leads to exon 26 skipping. In WS patient-derived fibroblasts, WRN-108 efficiently induced exon 27 skipping, restored WRN protein expression, and re-established its nuclear localization. Treatment improved cell proliferation and reduced senescence-associated markers, G-quadruplex accumulation, and γH2AX signaling, consistent with partial restoration of WRN-dependent genome maintenance functions. Topical administration in a rat skin wound model resulted in effective dermal penetration and sustained tissue retention. In a cynomolgus monkey wound model, WRN-108 induced exon 27 skipping in the skin and achieved dermal exposure without local toxicity. Short-term toxicity studies in mice and miniature pigs further confirmed its favorable tolerability. These findings provide preclinical evidence that ASO-mediated exon skipping can restore WRN function, highlighting the translational potential of WRN-108 as a therapeutic approach for refractory skin ulcers in WS patients harboring the c.3139-1G>C mutation.
2026-03-26 | Preferential correction of target genes by 5'-tailed duplexes with an antisense editor strand.
The correction (editing) of mutated genes at the DNA level is expected to cure gene-inherited diseases and cancers. A 5'-tailed duplex (TD) with an approximately 80-base editor strand (E-strand) plus a 35-base assistant strand (A-strand) was developed for gene editing without artificial nucleases. The E-strand has the normal (or desired) sequence and the A-strand hybridizes to the 3'-region of the E-strand. In this study, the polarity-dependency of gene editing by TDs was examined. The sense and antisense E-strands for eight transcribed target genes, including the WRN (Werner syndrome) gene, were designed, and the target plasmid DNAs were co-transfected with the TDs into human U2OS cells. Most TDs with the antisense E-strand corrected the targets more efficiently than those with the sense E-strand. However, transcription had only a slight effect on gene correction efficiency. These results suggested that the TDs containing the antisense E-strand are more useful editing tools than the sense TDs.
2025-05-18 | Macroscopic Analyses of RNA-Seq Data to Reveal Chromatin Modifications in Aging and Disease
Abstract Regulation of gene expression is fundamental for proper cellular function, and is constrained by the local chromatin environment of each gene, which varies spatially along the chromosome and is shaped by epigenetic modifications. Epigenetic modifications induce changes in the local chromatin structure, which can influence gene expression, by affecting the accessibility of DNA to transcription factors. Such changes are particularly relevant in aging and genetic disorders like Hutchinson-Gilford Progeria Syndrome (HGPS) and Werner Syndrome (WRN), where altered chromatin structure contributes to disease pathology. In this study, we analyze RNA-seq data using macroscopic metrics designed to be explicitly sensitive to chromatin modifications. The first metric, intra-chromosomal gene correlation length, measures spatial correlations in gene expressions along the chromosome. The second metric employs an energy landscape model based on the Arrhenius equation to estimate the energetic barriers associated with chromatin state transitions. We apply these metrics to various aging-related datasets, demonstrating their sensitivity to changes in the chromatin structure and the interpretability of the resulting outputs. The intra-chromosomal gene correlation length is particularly effective in quantifying changes in RNA-seq profiles due to increased chromatin accessibility during aging (and conversely, reduced accessibility due to treatment). This metric not only accurately distinguishes cell states, but also provides insight into the direction of aging. For instance, our observations on the effects of anti-sense oligonucleotide (ASO) treatment align with the existing literature, demonstrating that ASO partially restores chromatin structure in diseased cells. They additionally quantify the more pronounced effects in HGPS compared to WRN. The barrier energy landscape further extends this capability by offering a framework for understanding the progressive degradation of the regulatory mechanisms. Together, these metrics provide robust screening tools that enhance our ability to exploit common measurements such as RNA-seq to derive new phenotypes such as chromatin dynamics on aging and disease, offering an alternative perspective that complements traditional analytical techniques and enriches our understanding of cellular states.
2023-06-24 | WRNIP1 prevents transcription-associated genomic instability
ABSTRACT R-loops are non-canonical DNA structures that form during transcription and play diverse roles in various physiological processes. Disruption of R-loop homeostasis can lead to genomic instability and replication impairment, contributing to several human diseases, including cancer. Although the molecular mechanisms that protect cells against such events are not fully understood, recent research has identified the fork protection factors and the DNA damage response proteins as regulators of R-loop dynamics. Here, we identify the Werner helicase-interacting protein 1 (WRNIP1) as a novel factor that counteracts transcription-associated DNA damage upon replication perturbation. Loss of WRNIP1 leads to R-loop accumulation, resulting in collisions between the replisome and transcription machinery. We observe co-localization of WRNIP1 with transcription/replication complexes and R-loops after replication perturbation, suggesting its involvement in resolving transcription-replication conflicts. Moreover, WRNIP1-deficient cells show impaired replication restart from transcription-induced fork stalling. Notably, transcription inhibition and RNase H1 overexpression rescue all the defects caused by loss of WRNIP1. Importantly, our findings highlight the critical role of WRNIP1 ubiquitin-binding zinc finger (UBZ) domain in preventing pathological persistence of R-loops and limiting DNA damage, thereby safeguarding genome integrity.
proteins
2025-12-08 | Tumorigenic p53N236S balances aging and tumorigenesis via regulating DREAM/MMB and downstream telomere DNA replication pathways.
The Werner syndrome (WS) is characterized with both premature aging and tumorigenic phenotypes. In this study, we introduced a tumorigenic mutation p53N236S (referred to as p53S later), which is found in immortalized WS mouse embryo fibroblasts, back into WS mice to investigate its impact on the telomere dysfunction-induced aging process. Intriguingly, the introduction of p53S rescued the aging phenotypes of WS mice, showing the extension of the lifespan and the delay in organ degeneration. Further studies revealed that the introduction of p53S transcriptionally upregulated the DREAM/MMB pathway and downstream DNA helicases and telomere maintenance proteins, facilitated the recruitment of these proteins to G-quadruplex (G4) DNA structures proximal to DNA replication forks, and promoted the unwinding of G4. By comparing the cellular responses to pyridostatin and hydroxyurea, respectively, we confirmed that p53S specifically regulates G4-related DNA replication stress. Thus, p53S compensates the loss of Wrn and telomerase function, solves the DNA replication, telomere lengthening, and cell proliferation problems in WS cells, and ultimately rescues the aging phenotypes of WS. Together, our data indicate that certain tumorigenic features can be applied to balance with premature aging, rescuing the aging phenotype without tumorigenic risk. This study suggests a new mechanism in aging regulation and provides the possibility of developing a tumor-free longevity strategy and targeting G4 and DNA replication in aging-related tumor therapy.
2025-01-15 | Synergistic protection of nascent DNA at stalled forks by MSANTD4 and BRCA1/2-RAD51.
The regressed arms of reversed replication forks exhibit structural similarities to one-ended double-stranded breaks and need to be protected against uncontrolled nucleolytic degradation. Here, we identify MSANTD4 (Myb/SANT-like DNA-binding domain-containing protein 4), a functionally uncharacterized protein that uniquely counters the replication protein A (RPA)-Bloom (BLM)/Werner syndrome helicase (WRN)-DNA replication helicase/nuclease 2 (DNA2) complex to safeguard reversed replication forks from detrimental degradation, independently of the breast cancer susceptibility proteins (BRCA1/2)-DNA repair protein RAD51 pathway. MSANTD4 specifically interacts with the junctions between single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) in DNA substrates harboring a 3' overhang, which resemble the structural features of regressed arms processed by WRN-DNA2. This DNA-binding capability allows MSANTD4 to accumulate at reversed forks, strategically antagonizing the RPA-BLM/WRN-DNA2 complex by impeding its access to the ssDNA-dsDNA junction of the regressed arms. Loss of MSANTD4 exacerbates genome instability induced by replication stress in BRCA1/2-deficient cells. Our findings unveil a collaborative defense mechanism orchestrated by MSANTD4 and BRCA1/2-RAD51, effectively counteracting nucleolytic attacks on the regressed arms and synergistically preserving the integrity of reversed forks.
2024-09-29 | p21 Regulates Wnt-Notch balance via DREAM/MMB/Rb-E2F1 and maintains intestinal stem cell homeostasis.
The crosstalk and balance regulation of Wnt-Notch have been known to be essential for cell fate decision and tissue regeneration, however, how this balance is maintained and how the Wnt-Notch pathways are connected with cell cycle regulation is still not clear. By analyzing the molecular alterations in mouse model with accelerated aging phenotypes due to loss of p21 function in a Werner syndrome background, we observed that Wnt3 and β-Catenin were down-regulated, while Notch1 and Hes1 were up-regulated. This disruption in Wnt-Notch signaling was accompanied by the loss of intestinal stem cell compartment, increase in Bmi1 positive cells, loss of Olfm4/Lgr5 positive cells, and reduced secretory Paneth cells and goblet cells in the intestinal crypts of p21TKO mice. BrdU incorporation, cleaved caspase 3, and Tunel assay results revealed the fast turnover of intestinal epithelia, which may result in abnormal stem cell mobilization and exhaustion of the stem cell reservoir in the intestinal crypts. We further identified shift of DREAM complex towards MMB complex due to the loss of p21 as the cause for faster turnover of intestinal epithelia. Importantly, we identified the E2F1 as the transcriptional regulator for Notch1, which linked the p21-DREAM/MMB/Rb-E2F1 pathway with Wnt-Notch pathway. The overexpression of p21 rescued the DREAM pathway, as well as the imbalance of Wnt-Notch pathway. In summary, our data identify p21 as an important factor in maintaining sequential mobilization, proliferation, and homeostasis of intestinal stem cells.
2024-01-12 | O-09 A rare cause of acute pancreatitis: Werner Syndrome
Abstract Introduction Lipodystrophies are rare disorders characterized by loss of body fat resulting in leptin deficiency. Patients are predisposed to metabolic complications such as severe insulin resistance, hypertriglyceridemia, and hepatic steatosis. Werner syndrome (WS) is among the progeroid syndromes in the classification of lipodystrophy. Due to its extremely rare occurrence, it can often be overlooked by the clinician. Clinical Case A 19 years old male patient hospitalized for non-biliary acute pancreatitis was consulted for hypertriglyceridemia and hyperglycemia. He had no history of any disease or medication use. His sister was diagnosed with type 2 diabetes mellitus at age 29. She was using linagliptin and gliclazide for 3 years. She had short stature (147 cm) and low body weight (40 kg) and had scleroderma-like skin findings. The patient also had short stature (157 cm) and low body weight (41 kg). He had scleroderma-like skin findings and generalized loss of subcutaneous adipose tissue. The laboratory results were; glucose, 261 mg/dl; creatinine, 0.46 mg/dl; ALT, 24 U/l; lipase, 161 U/l; HbA1c, 9.6%; triglyceride, 799 mg/dl; HDL, 9.6 mg/dl; LDL, 75 mg/dl; c-peptide, 4.3 ng/dl. The thyroid function test results (TSH: 29.7 µIU/ml, fT4: 6.81 pmol/L, Anti-TPO: negative) were consistent with primary hypothyroidism. Hepatosteatosis was observed in abdominal ultrasonography. We initiated intensive insulin, metformin as well as fenofibrate and levothyroxine treatment. The patient needed high insulin doses (60 IU/day). Measured serum leptin levels were found to be low (2.11 ng/ml) in suspicion of lipodystrophy. Genetic analysis of the patient and his sister showed homozygous mutation in the WRN gene (c.1105C>T p.Arg369Ter, Homozygous) which was compatible with WS. The patient was started on leptin analog therapy in a clinical trial. Conclusion WS is an exceptionally rare autosomal recessive genetic disorder characterized by premature aging and multisystemic complications. The clinical features encompass scleroderma-like skin changes, short stature, low body weight, alopecia, cataracts, osteoporosis, and a propensity for atherosclerotic complications and malignancies. Impaired glucose tolerance is reported in 15%–20% of WS subjects, diabetes mellitus in 55%–70%, and dyslipidemia in 60%–85%. The presence of hypertriglyceridemia, diabetes mellıtus and generalized lack of subcutaneous adipose tissue led us to suspect from lipodystrophy. Although acute pancreatitis due to hypertriglyceridemia can be seen in lipodystrophy (15-20%), first presentation of WS presenting with acute pancreatitis is very rare in the literature. The most common mutation in non-Japanese patients in WRN gene is c.1105 C>T (18.6%). Metreleptin, an analog of human leptin, is shown to ameliorate the metabolic derangements. WS remains a diagnostic challenge due to its rarity, atypical presentation, and should be kept in mind in patients with severe dyslipidemia and insulin resistance.
2023-12-28 | Cellular Reprogramming, Transdifferentiation and Alleviation of the Aging Pathology
Cellular reprogramming and transdifferentiation have emerged as transformative technologies in regenerative medicine, holding significant promise for addressing age-related pathologies and rare genetic disorders. Dr. Shinya Yamanaka's pioneering work in cellular reprogramming paved the way for the restoration of pluripotency in terminally differentiated cells. The understanding that exogenous introduction of the key transcription factors (Oct4, Sox2, KLF4 and c-Myc) enables cells for reprogramming, regaining pluripotency has provided tremendous opportunities and better platforms for therapeutic implications. Transdifferentiation, the conversion of one differentiated cell type to another, offers a complementary approach to cellular reprogramming and can be procured by modulating the expression of specific transcription factors, miRNAs, or other small molecules. Therapeutic approaches that utilize transdifferentiated cells are promising in addressing the age-related pathologies of vital organs such as the pancreas, liver, cardiovascular system as well as neurological disorders. Additionally, the emerging field of epigenetic rejuvenation offers extended possibilities for targeted interventions as it focuses on targeting age-associated CpG signatures of the epigenome. Induced pluripotent stem cells (iPSCs) obtained by cellular reprogramming have become invaluable tools for studying rare monogenic syndromes and premature aging diseases that include Hutchinson-Gilford Progeria Syndrome (HGPS) and Werner syndrome. iPSCs enable researchers to model diseases and gain insights into their underlying mechanisms. Translation of these technologies into clinical practice just needs bypassing hurdles related to safe, efficient, specific therapeutic outcomes. Thus, recent advancements in stem cell technologies highlight that cellular reprogramming and transdifferentiation are poised to revolutionize healthcare, providing novel approaches to address age-related pathologies and other genetic disorders.
cell therapies
2024-01-31 | Sex-specific preservation of neuromuscular function and metabolism following systemic transplantation of multipotent adult stem cells in a murine model of progeria.
Onset and rates of sarcopenia, a disease characterized by a loss of muscle mass and function with age, vary greatly between sexes. Currently, no clinical interventions successfully arrest age-related muscle impairments since the decline is frequently multifactorial. Previously, we found that systemic transplantation of our unique adult multipotent muscle-derived stem/progenitor cells (MDSPCs) isolated from young mice-but not old-extends the health-span in DNA damage mouse models of progeria, a disease of accelerated aging. Additionally, induced neovascularization in the muscles and brain-where no transplanted cells were detected-strongly suggests a systemic therapeutic mechanism, possibly activated through circulating secreted factors. Herein, we used ZMPSTE24-deficient mice, a lamin A defect progeria model, to investigate the ability of young MDSPCs to preserve neuromuscular tissue structure and function. We show that progeroid ZMPST24-deficient mice faithfully exhibit sarcopenia and age-related metabolic dysfunction. However, systemic transplantation of young MDSPCs into ZMPSTE24-deficient progeroid mice sustained healthy function and histopathology of muscular tissues throughout their 6-month life span in a sex-specific manner. Indeed, female-but not male-mice systemically transplanted with young MDSPCs demonstrated significant preservation of muscle endurance, muscle fiber size, mitochondrial respirometry, and neuromuscular junction morphometrics. These novel findings strongly suggest that young MDSPCs modulate the systemic environment of aged animals by secreted rejuvenating factors to maintain a healthy homeostasis in a sex-specific manner and that the female muscle microenvironment remains responsive to exogenous regenerative cues in older age. This work highlights the age- and sex-related differences in neuromuscular tissue degeneration and the future prospect of preserving health in older adults with systemic regenerative treatments.
2022-10-28 | Research on Werner Syndrome: Trends from Past to Present and Future Prospects.
A rare and autosomal recessive premature aging disorder, Werner syndrome (WS) is characterized by the early onset of aging-associated diseases, including shortening stature, alopecia, bilateral cataracts, skin ulcers, diabetes, osteoporosis, arteriosclerosis, and chromosomal instability, as well as cancer predisposition. WRN, the gene responsible for WS, encodes DNA helicase with a 3' to 5' exonuclease activity, and numerous studies have revealed that WRN helicase is involved in the maintenance of chromosome stability through actions in DNA, e.g., DNA replication, repair, recombination, and epigenetic regulation via interaction with DNA repair factors, telomere-binding proteins, histone modification enzymes, and other DNA metabolic factors. However, although these efforts have elucidated the cellular functions of the helicase in cell lines, they have not been linked to the treatment of the disease. Life expectancy has improved for WS patients over the past three decades, and it is hoped that a fundamental treatment for the disease will be developed. Disease-specific induced pluripotent stem (iPS) cells have been established, and these are expected to be used in drug discovery and regenerative medicine for WS patients. In this article, we review trends in research to date and present some perspectives on WS research with regard to the application of pluripotent stem cells. Furthermore, the elucidation of disease mechanisms and drug discovery utilizing the vast amount of scientific data accumulated to date will be discussed.
2021-09-01 | Successful allogeneic stem cell transplantation of a patient with Werner syndrome and acute myeloid leukemia
• Werner syndrome is an adult-onset syndrome of accelerated aging predisposing to solid cancer and hematological malignancies. • Chemotherapy and stem cell transplantation was successful in a patient with Werner syndrome and AML. • Despite the poor risk profile, the patient remains in remission 5 years after transplantation and toxicity was acceptable.
2018-08-23 | Successful Cord Blood Transplantation in a Werner Syndrome Patient with High-risk Myelodysplastic Syndrome
Werner syndrome (WS) confers a high risk of the development of neoplasias, including hematological malignancies, and curative treatment for these malignancies is difficult to achieve. A 44-year-old man with myelodysplastic syndrome was admitted to our hospital. He was diagnosed with mutation-proven WS. He underwent cord blood transplantation (CBT) following fludarabine, busulfan, and melphalan administration. A chimerism analysis of his marrow blood on day 62 showed a donor pattern >95%, which confirmed engraftment. The patient lived for 15 months while maintaining remission of MDS without treatment-related toxicity. Our case shows that CBT can be a treatment modality for WS patients with hematological malignancies.
2015-01-29 | Werner Syndrome-specific induced pluripotent stem cells: recovery of telomere function by reprogramming
Werner syndrome (WS) is a rare human autosomal recessive premature aging disorder characterized by early onset of aging-associated diseases, chromosomal instability, and cancer predisposition. The function of the DNA helicase encoded by WRN, the gene responsible for WS, has been studied extensively. WRN helicase is involved in the maintenance of chromosome integrity through DNA replication, repair, and recombination by interacting with a variety of proteins associated with DNA repair and telomere maintenance. The accelerated aging associated with WS is reportedly caused by telomere dysfunction, and the underlying mechanism of the disease is yet to be elucidated. Although it was reported that the life expectancy for patients with WS has improved over the last two decades, definitive therapy for these patients has not seen much development. Severe symptoms of the disease, such as leg ulcers, cause a significant decline in the quality of life in patients with WS. Therefore, the establishment of new therapeutic strategies for the disease is of utmost importance. Induced pluripotent stem cells (iPSCs) can be established by the introduction of several pluripotency genes, including Oct3/4, Sox2, Klf4, and c-myc into differentiated cells. iPSCs have the potential to differentiate into a variety of cell types that constitute the human body, and possess infinite proliferative capacity. Recent studies have reported the generation of iPSCs from the cells of patients with WS, and they have concluded that reprogramming represses premature senescence phenotypes in these cells. In this review, we summarize the findings of WS patient-specific iPSCs (WS iPSCs) and focus on the roles of telomere and telomerase in the maintenance of these cells. Finally, we discuss the potential use of WS iPSCs for clinical applications.
small molecules
2026-08-13 | Discovery and Optimization of a WRN Helicase Inhibitor Series through Structure-Guided Drug Design from a Covalent Fragment Binding Insight.
WRN helicase activity inhibition has emerged as a promising therapeutic approach for targeting cancer cells with specific DNA repair deficiencies, especially those with microsatellite instability (MSI). Herein, we report a novel covalent WRN helicase inhibitor series discovered and optimized by leveraging insights from a covalent fragment investigation. Initial structure-based design led to potency-optimized compounds from this series that exhibited unbound cellular potency in the nanomolar range in both p21 induction and HCT116 CTG viability assays, albeit with high intrinsic warhead reactivity. Further refinement of the ADME properties by modulating the warhead reactivity yielded lead WC-2 with excellent cellular potency, low reactivity toward GSH, excellent plasma and blood stabilities, good oral bioavailability, and long in vivo half-lives in rat (T1/2 = 7.2 h; F = 62%) and dog (T1/2 = 18.9 h). WC-2 has the potential as a next-generation, low-dose WRN helicase clinical candidate for treating patients with MSI-classified tumors.
2026-08-04 | Data from Microsatellite Instable Cancer Cells Acquire On-target Resistance Mutations to WRN Helicase Inhibitors
<div>Abstract<p>The Werner syndrome helicase (WRN) is a promising target for cancers with microsatellite instability (MSI), leading to the initiation of at least five phase I clinical trials. Acquired resistance is a substantial obstacle to obtaining lasting benefits from targeted therapies in oncology and may be particularly acute in the setting of mismatch repair–deficient (dMMR) tumors, which can sample increased fitness landscapes owing to a higher mutational burden. In this study, we characterized resistance mechanisms using the clinical candidate HRO761 and two novel inhibitors in MSI cell lines and xenograft models. We observed the rapid emergence of resistance both <i>in vitro</i> and <i>in vivo</i>, with sequencing revealing clustered mutations within the <i>WRN</i> helicase domain. Computational structural analyses indicated that these mutations either directly interfere with inhibitor binding or alter the protein conformation required for inhibitor engagement. Notably, although most mutations conferred broad resistance across all three compounds, we identified specific alterations (L528S, C727R, and F730L) that exhibited selectivity between chemical scaffolds. This chemotype-specific resistance profile suggests opportunities for developing next-generation inhibitors that retain activity against resistant variants and for implementing rational treatment strategies with existing inhibitors. Overall, our findings demonstrate that on-target resistance to WRN inhibitors emerges rapidly in dMMR backgrounds but also highlight potential approaches to overcome resistance, supporting the continued development of WRN-targeted therapies for MSI cancers.</p></div>
2026-06-17 | Werner Syndrome: Symptoms, Hallmarks of Aging, Molecular Mechanisms and Therapeutic Pathway Inhibitors
Werner Syndrome (WS) is a rare autosomal recessive progeroid disorder characterized by accelerated aging and the premature onset of age-related conditions, such as stunted growth, cataracts, cardiovascular disease, malignancies, sarcopenia, osteoporosis, and diabetes. Clinical disease manifestations typically begin in adolescence to early adulthood, and result in a reduced lifespan compared to healthy individuals. WS arises from loss-of-function mutations in the WRN gene, which encodes a RecQ family helicase that has implications in DNA repair, replication, and telomere maintenance. Deficiency in functional RecQ helicase activity results in dysfunction that links WS to the hallmarks of aging, including genomic instability, telomere attrition, and premature cellular senescence. To date, there is no cure for WS, with current therapies primarily focusing on disease management through inhibition of important proteins in aging- and stress-related signaling pathways, namely mTOR and p38 MAPK. These emerging approaches have shown promising results in cellular models, but have yet to be tested in human clinical studies. This review therefore examines WS as a potential model for understanding the mechanisms of aging, and the implications of existing findings for informing new therapeutic strategies.
2026-06-12 | Functional orthogonality of WRN inhibitor resistance enables alternating therapy and mutation-tolerant inhibitor design in MSI-H cancers
Abstract Werner syndrome helicase (WRN) is a synthetic-lethal vulnerability in microsatellite instability–high (MSI-H)/mismatch repair–deficient (dMMR) cancers 1–5 , and non-covalent and covalent WRN inhibitors are now entering clinical development 6–9 . A central unresolved question is whether resistance to one WRN inhibitor class inevitably compromises the target, or instead creates actionable vulnerabilities to an alternate modality. Here we generated ten stable acquired-resistance models across three MSI-H cell lines using the non-covalent inhibitor HRO761 and the covalent inhibitor VVD-214. Whole-exome sequencing, biochemical reconstitution and isogenic knock-in models identified recurrent on-target WRN missense mutations as dominant resistance drivers, but with sharply modality-specific spectra: HRO761 resistance clustered at G729/F730/I852, whereas VVD-214 resistance concentrated at E846. These mutations impaired inhibitor engagement and abolished the canonical WRN inhibitor (WRNi)-induced pharmacodynamic cascade, including WRN reduction, DNA damage response (DDR) activation and G 2 /M arrest. Crucially, most resistance mutations retained biochemical, cellular and in vivo sensitivity to the alternate inhibitor modality, revealing a functional orthogonality that enabled a 7-day cyclic alternating regimen to delay tumour regrowth in xenografts. We further identified F730L as an engineered cross-resistant bottleneck model and used structure-guided, artificial intelligence (AI)-enabled optimization to generate GBA-007, a proof-of-concept mutation-tolerant WRN inhibitor candidate with promising activity against F730L in vitro and in vivo. Thus, clinically relevant WRN inhibitor classes impose distinct on-target resistance trajectories that can be exploited through schedule design, while cross-resistant bottlenecks can be addressed by rapid mutation-aware inhibitor engineering.
2026-06-03 | Structure-GuidedDiscovery of Potent, Selective, andOrally Bioavailable Werner Syndrome RecQ Helicase Inhibitors for theTreatment of Microsatellite Instability-High Tumors
Despite recent advances in immunotherapy for microsatellite instability-high (MSI-H) tumors, challenges of resistance persist, necessitating alternative therapeutic approaches. The synthetic lethal interaction between WRN helicase inhibition and MSI status presents a promising therapeutic strategy. Guided by the key structural features of the WRN-HRO761 complex, we rationally designed two classes of WRN inhibitorsspirocyclic compounds and benzo-fused heterocyclic analogsby targeting the solvent-exposed region. Among these, Q15 exhibited potent in vitro activity and excellent cellular selectivity. Compared with HRO761 in vivo, Q15 demonstrated more favorable oral pharmacokinetic properties and superior antitumor efficacy at 10 mg/kg, comparable efficacy at 20 mg/kg, and achieved complete tumor regression at 40 mg/kg. Preliminary safety evaluation further indicated that Q15 possesses a favorable safety profile. These findings support Q15 as a promising WRN inhibitor candidate for the treatment of MSI-H tumors.
gene therapies
2026-06-01 | WRN and Other RecQ Helicases in Life Cycles of Viruses
Abstract RecQ helicases are a conserved family of DNA-unwinding enzymes that play a key role in maintaining genomic stability by participating in DNA damage repair, recombination, replication, and telomere homeostasis. Five RecQ helicases are known in humans: BLM (the Bloom syndrome protein), WRN (Werner syndrome helicase), RECQL4, RECQL1, and RECQL5. All members of the RecQ family possess 3' → 5' helicase activity and are capable of unwinding DNA, including its complex secondary structures, in the 3'-to-5' direction by using the energy of ATP hydrolysis. WRN is unique among RecQ helicases in possessing additional 3' → 5' exonuclease activity, which expands its functionality in maintaining genomic stability. Mutations of the RecQ helicase genes lead to Werner, Bloom, and Rothmund–Thomson syndromes and are associated with a predisposition to cancer and premature aging. The enzymes consequently attract significant interest of the scientific community. Many viruses rely on host cell replication and repair mechanisms for their reproduction, and RecQ helicases may therefore influence the development of viral infections. The review discusses the role of RecQ helicases in replication of various viruses, including socially significant ones, such as the human immunodeficiency virus, herpes simplex virus, Epstein–Barr virus, hepatitis C virus, and others.
2025-08-05 | A case of rapid-progressing liver cirrhosis complicated by Werner syndrome.
Werner syndrome is a rare progeroid condition caused by a mutation in the WRN gene. It is characterized primarily by premature aging, diabetes mellitus, atherosclerosis, and an increased risk of malignancy. In this case, we present a man in his 40s with liver cirrhosis who was subsequently diagnosed with Werner syndrome. Shortly afterwards, he developed refractory ascites and a non-healing ulcer on his left big toe and ultimately died of liver failure. Despite having only mild fatty liver disease and being of normal weight, his liver became cirrhotic within a little over 4 years. Although a liver biopsy was not performed, the presumed etiology of his liver cirrhosis was non-alcoholic fatty liver disease (NAFLD) due to fatty liver disease. This case report highlights the importance of considering Werner syndrome in the differential diagnosis of fatty liver, particularly in the absence of obesity, as it can lead to the rapid progression of NAFLD-related liver cirrhosis.
2025-07-22 | Werner syndrome due to homozygous WRN mutation through chromosome 8 region of homozygosity in a consanguineous family.
An 18-year-old man showing growth retardation, progeroid facies and acral abnormalities was found to have Werner syndrome caused by a homozygous WRN mutation (c.502_503del) located within a 36.7-Mb region of homozygosity on chromosome 8.
2025-04-22 | Underlying data for Fig 5.
Human Werner syndrome (adult progeria, a well-established model of human aging) is caused by mutations in the Werner syndrome (WRN) gene. However, the expression patterns and functions of WRN in natural aging remain poorly understood. Despite the link between WRN deficiencies and progeria, our analyses of human colon tissues, mouse crypts, and Drosophila midguts revealed that WRN expression does not decrease but rather increases in intestinal stem cells (ISCs) with aging. Mechanistically, we found that the Drosophila WRN homologue (WRNexo) binds to Heat shock 70-kDa protein cognate 3 (Hsc70-3/Bip) to regulate the unfolded protein response of the endoplasmic reticulum (UPRER). Activation of the WRNexo-mediated UPRER in ISCs is required for ISC proliferation during injury repair. However, persistent DNA damage during aging leads to chronic upregulation of WRNexo in ISCs, where excessive WRNexo-induced ER stress drives age-associated gut hyperplasia in Drosophila. This study reveals how elevated WRNexo contributes to stem cell aging, providing new insights into organ aging and the pathogenesis of age-related diseases, such as colon cancer.
2025-01-24 | rDNA Copy Number Variation and Methylation During Normal and Premature Aging.
Ribosomal RNA is the main component of the ribosome, which is essential for protein synthesis. The diploid human genome contains several hundred copies of the rDNA transcription unit (TU). Droplet digital PCR and deep bisulfite sequencing were used to determine the absolute copy number (CN) and the methylation status of individual rDNA TU in blood samples of healthy individuals. The absolute CN ranged from 243 to 895 (median 469). There was no difference in absolute CN between males and females and no gain or loss of copies with age (15-71 years). The number of rDNA TU with a completely unmethylated (0%) or lowly methylated (1%-10%) promoter region significantly decreased, whereas the number of copies with higher (11%-100%) methylation increased with age. The number of presumably active TU with a hypomethylated (0%-10%) promoter varied from 94 to 277 (median 180), independent from absolute CN. In contrast, the number of inactive hypermethylated (11%-100%) copies strongly increased with absolute CN. Promoter hypermethylation compensates to some extent for the enormous CN variation among individuals. Patients with Werner syndrome, a premature aging syndrome displayed the same CN variation and age-related methylation changes as controls. The role of rDNA CN variation as a modulating factor in human health and disease is largely unexplored. In particular, very low and high CN may be associated with increased disease risk.
other
2026-08-12 | A skip in time: Frame-restoring exon skipping counters premature aging in Werner syndrome
Antisense oligonucleotide (ASO) technology is a blooming class of therapeutics quickly reaching the fame of gene therapy, offering potential for treating diseases by targeting RNA.1 Worthy of particular interest is the ability of ASOs to modulate splicing, thereby mediating exon skipping. The “skipping to correct a skip” strategy offers the advantage of producing a shorter but still functional protein; this is a clean-cut strategy able to overcome some of those mutations which compromise protein translation and/or functionality.
2026-05-07 | Development of an exon 27-skipping antisense oligonucleotide as a targeted therapy for refractory skin ulcers in Werner syndrome.
Werner syndrome (WS) is a rare autosomal recessive progeroid disorder caused by biallelic mutations in WRN and is frequently complicated by refractory skin ulcers for which no effective therapy exists. We developed WRN-108, a splice-switching antisense oligonucleotide (ASO) designed to induce exon 27 skipping and restore the open reading frame (ORF) disrupted by the most common WRN mutation in Japanese WS patients, c.3139-1G>C, which leads to exon 26 skipping. In WS patient-derived fibroblasts, WRN-108 efficiently induced exon 27 skipping, restored WRN protein expression, and re-established its nuclear localization. Treatment improved cell proliferation and reduced senescence-associated markers, G-quadruplex accumulation, and γH2AX signaling, consistent with partial restoration of WRN-dependent genome maintenance functions. Topical administration in a rat skin wound model resulted in effective dermal penetration and sustained tissue retention. In a cynomolgus monkey wound model, WRN-108 induced exon 27 skipping in the skin and achieved dermal exposure without local toxicity. Short-term toxicity studies in mice and miniature pigs further confirmed its favorable tolerability. These findings provide preclinical evidence that ASO-mediated exon skipping can restore WRN function, highlighting the translational potential of WRN-108 as a therapeutic approach for refractory skin ulcers in WS patients harboring the c.3139-1G>C mutation.
2026-03-26 | Preferential correction of target genes by 5'-tailed duplexes with an antisense editor strand.
The correction (editing) of mutated genes at the DNA level is expected to cure gene-inherited diseases and cancers. A 5'-tailed duplex (TD) with an approximately 80-base editor strand (E-strand) plus a 35-base assistant strand (A-strand) was developed for gene editing without artificial nucleases. The E-strand has the normal (or desired) sequence and the A-strand hybridizes to the 3'-region of the E-strand. In this study, the polarity-dependency of gene editing by TDs was examined. The sense and antisense E-strands for eight transcribed target genes, including the WRN (Werner syndrome) gene, were designed, and the target plasmid DNAs were co-transfected with the TDs into human U2OS cells. Most TDs with the antisense E-strand corrected the targets more efficiently than those with the sense E-strand. However, transcription had only a slight effect on gene correction efficiency. These results suggested that the TDs containing the antisense E-strand are more useful editing tools than the sense TDs.
2025-05-18 | Macroscopic Analyses of RNA-Seq Data to Reveal Chromatin Modifications in Aging and Disease
Abstract Regulation of gene expression is fundamental for proper cellular function, and is constrained by the local chromatin environment of each gene, which varies spatially along the chromosome and is shaped by epigenetic modifications. Epigenetic modifications induce changes in the local chromatin structure, which can influence gene expression, by affecting the accessibility of DNA to transcription factors. Such changes are particularly relevant in aging and genetic disorders like Hutchinson-Gilford Progeria Syndrome (HGPS) and Werner Syndrome (WRN), where altered chromatin structure contributes to disease pathology. In this study, we analyze RNA-seq data using macroscopic metrics designed to be explicitly sensitive to chromatin modifications. The first metric, intra-chromosomal gene correlation length, measures spatial correlations in gene expressions along the chromosome. The second metric employs an energy landscape model based on the Arrhenius equation to estimate the energetic barriers associated with chromatin state transitions. We apply these metrics to various aging-related datasets, demonstrating their sensitivity to changes in the chromatin structure and the interpretability of the resulting outputs. The intra-chromosomal gene correlation length is particularly effective in quantifying changes in RNA-seq profiles due to increased chromatin accessibility during aging (and conversely, reduced accessibility due to treatment). This metric not only accurately distinguishes cell states, but also provides insight into the direction of aging. For instance, our observations on the effects of anti-sense oligonucleotide (ASO) treatment align with the existing literature, demonstrating that ASO partially restores chromatin structure in diseased cells. They additionally quantify the more pronounced effects in HGPS compared to WRN. The barrier energy landscape further extends this capability by offering a framework for understanding the progressive degradation of the regulatory mechanisms. Together, these metrics provide robust screening tools that enhance our ability to exploit common measurements such as RNA-seq to derive new phenotypes such as chromatin dynamics on aging and disease, offering an alternative perspective that complements traditional analytical techniques and enriches our understanding of cellular states.
2023-06-24 | WRNIP1 prevents transcription-associated genomic instability
ABSTRACT R-loops are non-canonical DNA structures that form during transcription and play diverse roles in various physiological processes. Disruption of R-loop homeostasis can lead to genomic instability and replication impairment, contributing to several human diseases, including cancer. Although the molecular mechanisms that protect cells against such events are not fully understood, recent research has identified the fork protection factors and the DNA damage response proteins as regulators of R-loop dynamics. Here, we identify the Werner helicase-interacting protein 1 (WRNIP1) as a novel factor that counteracts transcription-associated DNA damage upon replication perturbation. Loss of WRNIP1 leads to R-loop accumulation, resulting in collisions between the replisome and transcription machinery. We observe co-localization of WRNIP1 with transcription/replication complexes and R-loops after replication perturbation, suggesting its involvement in resolving transcription-replication conflicts. Moreover, WRNIP1-deficient cells show impaired replication restart from transcription-induced fork stalling. Notably, transcription inhibition and RNase H1 overexpression rescue all the defects caused by loss of WRNIP1. Importantly, our findings highlight the critical role of WRNIP1 ubiquitin-binding zinc finger (UBZ) domain in preventing pathological persistence of R-loops and limiting DNA damage, thereby safeguarding genome integrity.
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
1 orphan drug designation for Werner syndrome.
1 orphan drug designation for Werner syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Progerinin | RNAs | FDA | 2020-02-05 | — | PRG S&T Co., Ltd. |
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.