RARE DISEASE
Dyskeratosis congenita
Dyskeratosis congenita
Dyskeratosis congenita
Synonyms: DC, DKC, Zinsser-Engman-Cole syndrome
Synonyms: DC, DKC, Zinsser-Engman-Cole syndrome
Synonyms: DC, DKC, Zinsser-Engman-Cole syndrome
Drug discovery
2
drugs
With orphan designations
Overview
Dyskeratosis congenita (DC) is a rare, multisystem telomere biology disorder characterized by the classic triad of nail dystrophy, lacy skin pigmentation, and oral leukoplakia. It predisposes to bone marrow failure (BMF), pulmonary fibrosis, and cancer (especially squamous cell carcinoma and hematologic malignancies). Caused by mutations in telomere-maintenance genes (TERT, TERC, DKC1, etc.), it follows X-linked, autosomal dominant, or recessive inheritance. Diagnosis combines clinical features, genetic testing, and telomere length analysis [1][2][4][13].
Burden
Leading causes of death: BMF (60–70%), pulmonary fibrosis (10–15%), and cancer (10%) [14][13].
High morbidity: Esophageal strictures (50% by adulthood), liver disease, and developmental delays in severe variants [7][19].
Progressive course with median survival often curtailed by complications [7][13].
Therapies
BMF management: Androgens (oxymetholone), hematopoietic growth factors (G-CSF), and hematopoietic stem cell transplant (HSCT) [12][13].
Emerging therapies: Preclinical Wnt pathway activation (e.g., lithium) reverses intestinal phenotypes [3][8].
Supportive care: Cancer surveillance, pulmonary/liver monitoring, and multidisciplinary follow-up [6][12].
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare hematological diseases, rare immunological diseases, rare neoplastic diseases, rare neurological diseases, rare ophthalmic disorders, rare skin diseases, rare transplant-related disorders
Research Papers
377 drug discovery papers about Dyskeratosis congenita, with 7 first-in-class and 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
377 drug discovery papers about Dyskeratosis congenita, with 7 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
2026-07-17 | Telomere and Aging Why Your Chromosome Has Shoelace TipsTelomeres—the repetitive nucleoprotein caps at the ends of linear chromosomes—function as protective "aglets" that prevent genomic instability and progressive DNA loss. This review synthesizes four decades of telomere research, from the discovery of the end‑replication problem to the latest insights into shelterin dynamics, telomerase regulation, and the non‑linear shortening of telomeres across the human lifespan. We critically examine the mechanistic links between telomere attrition, cellular senescence, oxidative stress, and mitochondrial dysfunction, and evaluate the evidence that positions telomere length as both a biomarker and a potential driver of biological aging. The clinical relevance of telomere biology is illustrated through disorders such as Dyskeratosis Congenita and the dual role of telomerase in cancer. Finally, we assess emerging interventions—from lifestyle modification to telomerase activators and gene‑editing approaches—and highlight key methodological pitfalls in telomere length measurement. By integrating structural, molecular, epidemiological, and clinical perspectives, this review provides a balanced, evidence‑based framework for understanding telomeres as central players in the aging process.
Telomeres—the repetitive nucleoprotein caps at the ends of linear chromosomes—function as protective "aglets" that prevent genomic instability and progressive DNA loss. This review synthesizes four decades of telomere research, from the discovery of the end‑replication problem to the latest insights into shelterin dynamics, telomerase regulation, and the non‑linear shortening of telomeres across the human lifespan. We critically examine the mechanistic links between telomere attrition, cellular senescence, oxidative stress, and mitochondrial dysfunction, and evaluate the evidence that positions telomere length as both a biomarker and a potential driver of biological aging. The clinical relevance of telomere biology is illustrated through disorders such as Dyskeratosis Congenita and the dual role of telomerase in cancer. Finally, we assess emerging interventions—from lifestyle modification to telomerase activators and gene‑editing approaches—and highlight key methodological pitfalls in telomere length measurement. By integrating structural, molecular, epidemiological, and clinical perspectives, this review provides a balanced, evidence‑based framework for understanding telomeres as central players in the aging process.
2026-06-02 | The R2T(P) complex orchestrates the SHQ1 driven early steps of box H/ACA snoRNP maturation
Abstract The chaperones RuvBL1 and RuvBL2 are members of the AAA+ ATPase family and participate in diverse cellular processes, including DNA repair, transcriptional regulation, and assembly of macromolecular complexes such as snoRNPs. The biogenesis of box H/ACA snoRNPs additionally requires the assembly factor SHQ1. These protein-RNA complexes are essential for ribosome biogenesis and telomerase stability and are linked to diseases such as dyskeratosis congenita and cancer. Despite detailed knowledge of mature complexes, their assembly mechanisms and how they can be modulated remain unclear. We characterize a trimeric interaction between SHQ1 and RuvBL1:RuvBL2, providing insight into early maturation of the protein-only precursor of box H/ACA snoRNPs. SHQ1 binds the flexible domain II of RuvBL1:RuvBL2, corresponding to the dodecamerization interface, suggesting disruption of this interface and promotion of hexamer formation. We further purified a complex containing RuvBL1:RuvBL2, SHQ1, and DKC1, the catalytic component of H/ACA snoRNPs and a client of SHQ1. This demonstrates that SHQ1 and DKC1 can simultaneously associate with RuvBL1:RuvBL2, potentially facilitating DKC1 release and subsequent snoRNA binding. Additionally, we identified a direct interaction between SHQ1 and RPAP3, a co-chaperone of RuvBL1:RuvBL2 (within the R2TP). Hence, RPAP3 may be responsible for recruiting SHQ1:DKC1 to hexameric RuvBL1:RuvBL2 and/or assist in the AAA+ mediated dissociation of the dimer. Since SHQ1 shares a domain with PIH1D1, an integral member of the R2TP complex, our findings suggest that early H/ACA snoRNP maturation may involve the R2T instead of the previously proposed R2TP complex.
2026-04-25 | Mathematical modelling of premature haematopoietic ageing in dyskeratosis congenita.
Idiopathic dyskeratosis congenita (DC) is a disorder characterized by mucocutaneous alterations, bone-marrow failure, immune deficiency, liver cirrhosis, and other morbidities, due to alterations in telomere maintenance, which, in most cases, lead to short telomeres and poor tissue regeneration and function. The main cause of mortality is bone-marrow failure. A non-local diffusion-advection model with zero-flux boundary conditions is used to simulate the generational and temporal evolution of a hematopoietic stem cell (HSC) population in order to investigate the progression of DC. Blood-cell production from progenitor cells that had exited the HSC compartment was quantified. The influence of variations in initial proliferation potential ([Formula: see text]) and telomerase activity (s) on the onset of pancytopenia was examined. Age-and weight-dependent blood cell demands are modeled for both sexes, establishing a physiological baseline against which DC-related deficiencies are compared. Simulations revealed that lower [Formula: see text] values and reduced telomerase activity accelerate stem cell exhaustion, resulting in early pancytopenia, sometimes before age of 2 years. In contrast, patients with moderately higher [Formula: see text] values developed pancytopenia later in life, with onset delayed until the third or fourth decade. Treatment simulations demonstrated that a two-year course of danazol, a synthetic androgen, can slow telomere attrition. These findings suggest that pharmacological intervention may delay hematopoietic failure and possibly improve the production of oocytes with better-preserved telomeres in female DC patients. Our model provides a valuable framework for assessing (or understanding, or both) disease progression and evaluating therapeutic strategies in telomeropathy-associated bone marrow failure.
2026-03-29 | Bone marrow failure in telomere biology disorders: Current understanding and the emerging landscape of non-transplant therapies.
Telomere biology disorders (TBDs) are a heterogeneous group of inherited systemic diseases caused by pathogenic variants in genes encoding telomerase or proteins involved in telomere maintenance or protection. With very short and/or dysfunctional telomeres, patients with TBD have clinical manifestations clustered in tissues with high rates of cell proliferation. Bone marrow failure (BMF) is the most common hematologic complication of a TBD and can precede the development of more difficult-to-treat malignant transformation. However, not all patients with TBD develop BMF, and some genotype/phenotype correlations are emerging. While allogeneic hematopoietic cell transplant (HCT) is curative for BMF in TBD, toxicities of the conditioning regimen can be detrimental to other organs. Balancing the risk of malignant transformation with HCT toxicity is a core challenge for providers who care for patients with TBD-associated BMF. Herein, we review the clinical presentation, pathophysiology, surveillance, and non-HCT treatment of BMF in TBD, including supportive care, androgens, thrombopoietin receptor agonists, and investigational approaches.
2026-01-07 | A rare case of dyskeratosis congenita with DKC1 mutation presenting initially as thrombocytopenia: Case report.
Dyskeratosis congenita is a rare genetic disorder classically characterized by the mucocutaneous triad and bone marrow failure. Diagnosis is challenging when hematologic manifestations precede classic features. A 10-year-old male initially presented with isolated thrombocytopenia, which was misdiagnosed as aplastic anemia. Retrospective examination revealed the mucocutaneous triad. Genetic testing confirmed a pathogenic hemizygous DKC1 mutation (c.1058C>T, p.A353V). The patient received a 3-month course of androgen therapy. Genetic counseling and prenatal testing were conducted for the family. Androgen therapy maintained platelets at 30-60 × 109/L without bleeding or adverse events during follow-up. The asymptomatic mother was a heterozygous carrier. Prenatal testing identified the same mutation in a male fetus, leading to pregnancy termination at 24 weeks. Dyskeratosis congenita can present with isolated cytopenia, risking misdiagnosis. Early genetic confirmation is vital for management and enables informed reproductive planning through prenatal diagnosis. Androgen therapy may be an effective supportive treatment.
cell therapies
2026-01-01 | Umbilical Cord Blood Transplantation for Patients with Idiopathic and Inherited Bone Marrow Failure Disorders
Abstract Umbilical cord blood transplantation (UCBT) offers a viable hematopoietic stem cell source for patients with idiopathic and inherited bone marrow failure (BMF) syndromes lacking matched related donors (MRDs) or matched unrelated donors (MUDs). Although its use has declined with the rise of haploidentical transplantation, UCBT remains crucial for select patients, especially children. The approach is associated with rapid donor availability, low graft versus host disease (GvHD) risk, and favorable outcomes in matched settings. Retrospective data and prospective trials demonstrate encouraging survival, particularly with appropriate cell dose, minimal human leukocyte antigen (HLA) mismatch, and fludarabine (Flu)-based reduced-intensity conditioning (RIC) regimens. Specific syndromes such as Fanconi anemia (FA), severe aplastic anemia (SAA), dyskeratosis congenita (DC), and Diamond–Blackfan anemia (DBA) highlight distinct challenges and considerations in UCBT application. While matched sibling UCBT shows excellent outcomes, unrelated UCBT requires careful patient selection and transplant expertise. As research advances and transplant protocols evolve, UCBT remains a critical option in the curative landscape for patients with BMF syndromes.
2025-10-18 | Hematopoietic cell transplantation in inherited bone marrow failure syndromes
Inherited bone marrow failure syndromes (IBMFS) comprise a heterogeneous group of rare genetic disorders characterized by defective hematopoiesis, congenital anomalies, and a predisposition to clonal evolution and malignancies. Hematopoietic cell transplantation remains the only curative option for the hematologic manifestations of these disorders, although it does not correct congenital malformations or eliminate the long-term risk of non-hematopoietic cancers. This review summarized current evidence and transplantation strategies for major IBMFS, including Fanconi anemia, dyskeratosis congenita/telomere biology disorders, Diamond-Blackfan anemia, Shwachman-Diamond syndrome, congenital neutropenia, congenital amegakaryocytic thrombocytopenia, and other inherited thrombocytopenias. We discussed disease-specific transplant indications, donor selection, conditioning regimens, graft source preferences, and outcomes across different patient populations. Advances in reduced-intensity conditioning and post-transplant cyclophosphamide have expanded donor availability, improving survival even with alternative donors. Nevertheless, long-term challenges persist, such as increased risks of solid tumors, endocrine dysfunction, and organ toxicity, emphasizing the need for multidisciplinary care and lifelong surveillance. Optimal outcomes depend on timely referral to specialized centers, meticulous donor screening, and individualized transplant strategies tailored to the unique biology of each disorder.
2025-07-08 | Telomere Biology Disorder Predisposition in Bone Marrow Failure and Clonal Hematopoiesis
Abstract Telomere biology disorders (TBDs), exemplified by dyskeratosis congenita (DC), are characterized by genetic defects in telomere maintenance genes, leading to telomere attrition and multi-organ manifestations including bone marrow failure (BMF) and increased malignancy risk. This study aimed to evaluate the prevalence and clinical impact of rare possibly significant variations (PSVs) in telomere-related genes among patients with BMF and clonal hematopoiesis disorders. We analyzed 1320 patients diagnosed with aplastic anemia, myelodysplastic syndrome, acute myeloid leukemia, or acute lymphoblastic leukemia and identified 113 PSVs in 103 patients, significantly exceeding the prevalence in the general population (gnomAD). The most frequently mutated genes were RTEL1 (37%) and CTC1 (30%). While missense variants predominated, novel variants accounted for approximately 27.4%. Patients harboring PSVs exhibited significantly shorter telomeres compared to unaffected relatives, reinforcing telomere length as a critical functional biomarker. Telomere-mediated genetic anticipation was clearly evident: younger patients had notably shorter telomeres compared to their older first-degree relatives, reflecting cumulative generational telomere attrition and progressively severe phenotypes. Despite variability in clinical presentations—with many patients lacking classical mucocutaneous or fibrotic manifestations—telomere shortening provided robust onset information. Our findings emphasize the importance of integrating genetic testing and telomere length measurement into clinical practice for early diagnosis, personalized risk stratification, and tailored management, including reduced-intensity conditioning transplantation and emerging targeted therapies.
2025-03-10 | Haploidentical Hematopoietic Cell Transplantation in Dyskeratosis Congenita with Myelodysplastic Syndrome/Acute Myeloid Leukemia.
Allogeneic hematopoietic cell transplantation (Allo-HCT) is the only curative option for marrow failure, myelodysplastic syndrome (MDS), and acute myeloid leukemia associated with dyskeratosis congenita (DKC). Due to chromosomal instability and sensitivity to radiation and alkylating agents, HCT is associated with a high incidence of transplant-related mortality in DKC. A 25-year-old male presented with DKC-associated cutaneous manifestations and myelodysplastic syndrome / acute myelogenous leukemia (MDS/AML). Targeted next-generation sequencing revealed mutation of the DKC1 and RUNX1 genes. His mother and sibling sisters were carriers for the DKC1 mutation. Due to high donor-specific antibody mean fluorescence intensity (DSA-MFI) against the unshared Human Leukocyte Antigen-A (HLA-A) allele of his 6/12 HLA-matched father, his paternal cousin's sister was selected as a haploidentical (6/12 HLA-matched) donor for HCT. He underwent allo-HCT with stable disease burden using a specifically-designed RIC regimen containing treosulfan (at 50% reduced dosing), fludarabine, and rabbit anti-thymocyte globulin. The graft versus host disease (GVHD) prophylaxis contained reduced-dose post-transplant cyclophosphamide (PTCy dose reduction of 50%) with mycophenolate mofetil and cyclosporine. He engrafted with complete donor chimerism, and the day +30 marrow was in complete morphological remission with undetectable measurable residual disease by flow cytometry. On day +126, he developed steroid-responsive late-onset grade II acute GVHD (stage III skin GVHD). He suffered from morphologic relapse on day +220 and succumbed from sepsis with septic shock on day +256. This case demonstrates the safety and feasibility of haploidentical-HCT using a treosulfan-based reduced-intensity conditioning (RIC) regimen and modified PTCy-based GVHD prophylaxis in DKC. Disease relapse in this patient underscores the impact of pretransplant disease burden on relapse free survival in DKC patients with MDS/AML who are not eligible for myeloablative conditioning.
2025-02-25 | Clinical Use of ZSCAN4 for Telomere Elongation in Hematopoietic Stem Cells.
Extremely short telomeres in patients with dyskeratosis congenita and related telomere biology disorders (TBDs) lead to premature cellular senescence and bone marrow failure. Zinc finger and SCAN domain-containing 4 (ZSCAN4) elongates telomeres by recombination. We report a clinical study in which EXG34217, the term given for autologous CD34+ hematopoietic stem cells from patients with TBD exposed to a temperature-sensitive Sendai virus vector encoding human ZSCAN4 at 33°C for 24 hours, was infused into patients without preconditioning. Four patients were enrolled; two experienced successful CD34+ mobilization during the second mobilization attempt and underwent apheresis and EXG34217 infusion, with follow-up of 5 and 24 months (both ongoing). We observed telomere elongation (1.06- to 1.34-fold) in CD34+ cells ex vivo. In one patient, the treatment was associated with a change in the mean absolute neutrophil count (ANC) from 1.78×103 to 3.18×103 cells/μl; the lymphocyte subpopulation telomere length changed from 3.6 to 6.7 kb (50th percentile for age). In the other patient, the treatment was associated with a change in the lowest ANC from 0.6×103/μl to 1.2×103/μl; this has occurred in 5 months without the patient receiving prior intermittent low-dose granulocyte-colony-stimulating factor injections. During mobilization, all patients experienced mild to moderate bone pain or pain after line replacement, and one patient had a blood infection associated with fever and hypoxemia. After EXG34217 infusion, no acute safety issues were noted; in one patient mild to moderate long-term cardiac and pulmonary adverse events were noted; these were similar to symptoms of the patient's underlying conditions. Although definitive conclusions cannot be drawn from the two EXG34217-treated patients, these results warrant further investigation of CD34+ cells exposed to ZSCAN4 for treating TBDs. (Funded by Elixirgen Therapeutics; ClinicalTrials.gov number, NCT04211714.).
gene therapies
2026-08-07 | The potential of gene therapy to rescue telomeric and extratelomeric defects in X-linked dyskeratosis congenita.
Dyskeratosis congenita (DC) is a rare inherited disorder characterized by bone marrow failure, pulmonary fibrosis, and cancer predisposition. X-linked DC (X-DC) is caused by mutations in the DKC1 gene, which encodes dyskerin, a multifunctional protein that is essential for telomere maintenance and multiple RNA-associated processes. Here, we first generated human X-DC HSPC models by introducing DKC1 frameshift mutations or the hypomorphic c.196 A>G mutation, into cord blood CD34+ cells from healthy male donors. These X-DC-like HSPCs recapitulated key hematopoietic features of the disease, including impaired proliferation, defective telomere maintenance and altered rRNA maturation. To correct these defects, lentiviral vectors were constructed carrying DKC1 under the PGK promoter or a weaker promoter driven by TERC regulatory sequences. While PGK-driven expression of dyskerin only restored the proliferation of X-DC-like HSPCs, pTERC-mediated expression of dyskerin also corrected the telomere maintenance and rRNA maturation defects characteristic of X-DC cells, without altering the functional properties of healthy HSPCs. These findings indicate that TERC promoter-driven dyskerin expression can functionally rescue key telomeric and extratelomeric defects in HSPCs carrying frameshift or hypomorphic DKC1 mutations, supporting further preclinical development of this strategy and providing a rationale for its evaluation as a therapeutic approach for X-linked dyskeratosis congenita.
2026-05-01 | C29-13 Somatic Variants Rescue Bone Marrow Failure, But Not Lung Disease in Patients With Germline Variants in TINF2
Abstract Introduction Telomeres are essential for genome maintenance. Rare variants disrupting telomere maintenance genes cause a spectrum of short telomere syndromes, with idiopathic pulmonary fibrosis (IPF) as the most common phenotype. Variants in the shelterin component TIN2 typically cause severe pediatric dyskeratosis congenita (DC) and bone marrow failure. However, a subset of patients with germline TINF2 variants presents with less severe, adult-onset disease, including IPF, suggesting the presence of modifying factors. Methods We identified three patients with pathogenic germline TINF2 hotspot variants evaluated at the University of Pittsburgh Medical Center for lung transplantation. Two had a family history of DC; one had a sporadic presentation. Clinical genetic testing and deep exome sequencing was used to identify somatic variants. We validated the function of somatic variants in vitro using CRISPR/Cas9-mediated genome editing in multiple cell lines and in patient-derived induced pluripotent stem cells (iPSCs). Results All three patients had somatic variants in the DNA-binding domain of POT1 where tumor-specific variants have been previously reported. Edited cells showed no signs of DNA damage, genomic instability, or altered growth kinetics. Telomeres progressively lengthened in all edited lines. iPSCs reprogrammed from patient PBMCs, which harbored both the germline TINF2 and somatic POT1 variants, also demonstrated gradual telomere lengthening, verifying the POT1 variants are functional and sufficient for telomere elongation, even in the context of the pathogenic TINF2 variant. Conclusions Somatic POT1 variants appear to rescue hematopoietic function and cause telomere lengthening in vitro. POT1 editing is efficient and does not appear to influence genome stability. We propose that genetically modifying POT1 may be an effective therapy to rescue the bone marrow of patients with short telomeres. This abstract is funded by: NA
2026-01-02 | Oral squamous cell carcinoma risk and magnitude of association in inherited cancer predisposition syndromes: evidence from a large real-world cohort.
Inherited cancer predisposition syndromes (ICPS) are rare genetic disorders associated with an elevated cancer risk. This study evaluates oral squamous cell carcinoma (OSCC) prevalence across selected ICPS, including Fanconi anemia (FA), Plummer-Vinson syndrome, Cowden syndrome, Li-Fraumeni syndrome, dyskeratosis congenita, and xeroderma pigmentosum, quantifies risk magnitude, examines age at diagnosis, and assesses tobacco's modifying effect on OSCC risk in these populations. We conducted a retrospective cohort study using the TriNetX Research Network, including patients with or without ICPS identified by ICD‑10 codes over a 20‑year period. OSCC cases were matched 1:1 by age and sex to controls. The analyses assessed prevalence, odds ratios, age at diagnosis, and the impact of tobacco use. Statistical significance was set at P < .05. The prevalence of OSCC among ICPS patients ranged from 0.11% to 4.66%, with the highest in patients with FA. Among ICPS, only FA showed a markedly increased OSCC risk (OR = 40.63, P < .01), while Plummer-Vinson syndrome and dyskeratosis congenita were inversely associated. Patients with ICPS developed OSCC at younger ages (P < .0001). Smoking increased OSCC risk within ICPS (OR = 1.47), whereas nonsmokers with ICPS had a reduced risk (OR = 0.78). FA is strongly associated with OSCC; OSCC also occurs in Li-Fraumeni syndrome and Cowden syndrome. Patients with ICPS present with OSCC at a younger age, supporting targeted screening for high‑risk ICPS populations.
2025-12-10 | Fueling for the finish line: Control of human telomerase activity by nucleotide metabolism.
Telomeres are repetitive DNA sequences that preserve genome integrity. Human telomere length is kept in a tight window through a balance between telomere erosion during genome replication and telomere elongation by the telomerase reverse transcriptase. In humans, genetically determined telomere length is associated with lifespan, while inherited defects in telomere length maintenance genes predispose to a spectrum of lethal diseases termed telomere biology disorders (TBDs). Recently, dNTP metabolism has emerged as a previously underappreciated pathway that is critical for human telomerase regulation and telomere length control. Genome-wide association studies have implicated variation in several dNTP metabolism genes with human telomere length. Genetic variants at the TYMS locus, which encodes the rate limiting thymidine synthesis enzyme thymidylate synthase, have been shown to cause the TBD dyskeratosis congenita. Genome-wide CRISPR/Cas9 functional screening has linked telomere length control to multiple key dNTP metabolism genes. Remarkably, mechanistic studies emerging from these genetic data have revealed a profound, bidirectional sensitivity of human telomerase activity to cellular dNTP levels, that is readily manipulated through several metabolic control nodes. Here, we review the emerging genetic evidence and mechanistic studies supporting the relationship between dNTP metabolism and telomere length control. We present an integrated model for human telomerase regulation, wherein the levels of dNTP substrates govern telomerase reverse transcriptase activity and in turn human telomere length. We discuss the therapeutic prospects and recent trials for manipulating dNTP metabolism to treat TBDs and related degenerative diseases.
2025-12-03 | CRISPR–Cas9 mediated gene therapy in inherited bone marrow failure syndromes
Introduction This systematic review evaluates CRISPR–Cas9 mediated gene therapy for inherited bone marrow failure syndromes, a heterogeneous group of rare inherited disorders characterised by cytopenia, cancer predisposition, and multi-organ involvement, for which supportive care and allogeneic haematopoietic stem cell transplantation provide cures for some but remain imperfect, donor-limited, and associated with significant morbidity. The objective of this review is to evaluate the current state of CRISPR–Cas9 mediated gene therapy in inherited bone marrow failure syndromes, with a focus on how this technology has been applied in experimental models to correct pathogenic mutations and restore haematopoietic function. Methods We searched PubMed, Scopus, and Google Scholar for studies combining inherited bone marrow failure syndromes with gene editing, prime editing, base editing, or CRISPR–Cas9. Results Of 876 records screened, 18 met the inclusion criteria. Fanconi anaemia predominated (n=8), with additional work in severe congenital neutropenia (n=3), Shwachman–Diamond syndrome (n=2), Diamond–Blackfan anaemia (n=2), and single studies in dyskeratosis congenita, congenital amegakaryocytic thrombocytopenia, and myelodysplastic syndrome/ acute myeloid leukaemia predisposition. Discussion Overall, CRISPR–Cas9 has demonstrated feasibility for ex vivo correction in inherited bone marrow failure syndromes; however, future clinical adaptation will depend on overcoming key hurdles, such as careful assessment of off-target effects and establishing regulatory pathways that enable access for patients with rare diseases, thereby bridging the gap between preclinical and therapeutic application.
oligonucleotides
2023-10-02 | LARP3, LARP7, and MePCE are Involved in the Early Stage of Human Telomerase RNA Biogenesis
Human telomerase assembly is a highly dynamic process. Using biochemical approaches, we found that LARP3 and LARP7/MePCE are involved in the early stage and that their binding to hTR is destabilized when the mature hTR is produced. LARP7 and MePCE knockdown inhibits the conversion of the 3′-extended short (exS) form into mature hTR and the cytoplasmic accumulation of hTR, resulting in telomere shortening. LARP3 plays a negative role in preventing the processing of the 3′-extended long (exL) form and binding of LARP7 and MePCE. Interestingly, the tertiary structure of the exL form prevents LARP3 binding and facilitates hTR biogenesis. Supporting this process, LARP3 at low levels promotes hTR maturation, increases telomerase activity, and elongates telomeres. Our data suggest that LARP3 and LARP7/MePCE mediate the processing of hTR precursors and thus control the production of functional telomerase.
2023-09-22 | Telomerase RNA-based aptamers restore defective myelopoiesis in congenital neutropenic syndromes
Telomerase RNA (TERC) has a noncanonical function in myelopoiesis binding to a consensus DNA binding sequence and attracting RNA polymerase II (RNA Pol II), thus facilitating myeloid gene expression. The CR4/CR5 domain of TERC is known to play this role, since a mutation of this domain found in dyskeratosis congenita (DC) patients decreases its affinity for RNA Pol II, impairing its myelopoietic activity as a result. In this study, we report that two aptamers, short single-stranded oligonucleotides, based on the CR4/CR5 domain were able to increase myelopoiesis without affecting erythropoiesis in zebrafish. Mechanistically, the aptamers functioned as full terc; that is, they increased the expression of master myeloid genes, independently of endogenous terc, by interacting with RNA Pol II and with the terc-binding sequences of the regulatory regions of such genes, enforcing their transcription. Importantly, aptamers harboring the CR4/CR5 mutation that was found in DC patients failed to perform all these functions. The therapeutic potential of the aptamers for treating neutropenia was demonstrated in several preclinical models. The findings of this study have identified two potential therapeutic agents for DC and other neutropenic patients.
2023-09-17 | CRISPR screen identifies CEBPB as contributor to dyskeratosis congenita fibroblast senescence via augmented inflammatory gene response.
Abstract Aging is the consequence of intra- and extracellular events that promote cellular senescence. Dyskeratosis congenita (DC) is an example of a premature aging disorder caused by underlying telomere/telomerase-related mutations. Cells from these patients offer an opportunity to study telomere-related aging and senescence. Our previous work has found that telomere shortening stimulates DNA damage responses (DDRs) and increases reactive oxygen species (ROS), thereby promoting entry into senescence. This work also found that telomere elongation via TERT expression, the catalytic component of the telomere-elongating enzyme telomerase, or p53 shRNA could decrease ROS by disrupting this telomere–DDR–ROS pathway. To further characterize this pathway, we performed a CRISPR/Cas9 knockout screen to identify genes that extend life span in DC cells. Of the cellular clones isolated due to increased life span, 34% had a guide RNA (gRNA) targeting CEBPB, while gRNAs targeting WSB1, MED28, and p73 were observed multiple times. CEBPB is a transcription factor associated with activation of proinflammatory response genes suggesting that inflammation may be present in DC cells. The inflammatory response was investigated using RNA sequencing to compare DC and control cells. Expression of inflammatory genes was found to be significantly elevated (P < 0.0001) in addition to a key subset of these inflammation-related genes [IL1B, IL6, IL8, IL12A, CXCL1 (GROa), CXCL2 (GROb), and CXCL5]. which are regulated by CEBPB. Exogenous TERT expression led to downregulation of RNA/protein CEBPB expression and the inflammatory response genes suggesting a telomere length-dependent mechanism to regulate CEBPB. Furthermore, unlike exogenous TERT and p53 shRNA, CEBPB shRNA did not significantly decrease ROS suggesting that CEBPB's contribution in DC cells’ senescence is ROS independent. Our findings demonstrate a key role for CEBPB in engaging senescence by mobilizing an inflammatory response within DC cells.
2023-07-31 | Control of protein synthesis through mRNA pseudouridylation by dyskerin.
Posttranscriptional modifications of mRNA have emerged as regulators of gene expression. Although pseudouridylation is the most abundant, its biological role remains poorly understood. Here, we demonstrate that the pseudouridine synthase dyskerin associates with RNA polymerase II, binds to thousands of mRNAs, and is responsible for their pseudouridylation, an action that occurs in chromatin and does not appear to require a guide RNA with full complementarity. In cells lacking dyskerin, mRNA pseudouridylation is reduced, while at the same time, de novo protein synthesis is enhanced, indicating that this modification interferes with translation. Accordingly, mRNAs with fewer pseudouridines due to knockdown of dyskerin are translated more efficiently. Moreover, mRNA pseudouridylation is severely reduced in patients with dyskeratosis congenita caused by inherited mutations in the gene encoding dyskerin (i.e., DKC1). Our findings demonstrate that pseudouridylation by dyskerin modulates mRNA translatability, with important implications for both normal development and disease.
2021-03-16 | Upregulation of miR‑126 inhibits podocyte injury in sepsis via EGFL6/DKC1 signaling pathway
Sepsis‑induced cardiorenal syndrome is one of the multiple organ dysfunctions observed in sepsis. It is determined by a primary dysfunction in one organ that leads to secondary injury to another organ. Studies have shown the involvement of microRNAs (miRs) in the diagnosis and prognosis of several pathologies. However, the implication of miR‑126 in the podocyte damage associated with sepsis has not been evaluated until now. In the current study, the miR‑126 expression was downregulated in a podocyte injury model together with downregulation of nephrin expression. The transfection of podocytes from podocyte injury group with miR‑126 mimics demonstrated an increase in cell proliferation and a decrease in cell apoptosis. Bioinformatics analysis predicted that the target of miR‑126 was epidermal growth factor‑like domain multiple 6 (EGFL6) and dyskeratosis congenita 1 (DKC1) and these were confirmed by dual‑luciferase reporter assay. miR‑126 upregulation determined EGFL6 and DKC1 upregulation and prevented podocyte injury. The current study demonstrated that overexpression of miR‑126 could protect podocytes from sepsis‑induced injury through an EGFL6/DKC1 signaling pathway.
other
2026-04-15 | Adriamycin, Vinblastine and Dacarbazine With Immunotherapy Achieves Complete Metabolic Response in a Patient With Classical Hodgkin Lymphoma and Dyskeratosis Congenita.
Dyskeratosis congenita (DC) is a rare inherited telomeropathy characterized by defective telomere maintenance and an elevated risk of hematologic malignancies. Classical Hodgkin lymphoma (cHL) is a rare malignancy described in patients with DC, and optimal treatment remains undefined due to overlapping toxicities of standard ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) and radiation therapy in this high-risk population. We present a 48-year-old man with longstanding thrombocytopenia who was diagnosed with DC based on clinical features and genetic testing. Two years post diagnosis, he developed stage IIA bulky cHL (nodular sclerosing, CD30+, Epstein-Barr virus (EBV)+). To mitigate pulmonary and myelotoxicity risks, he received a modified regimen of brentuximab vedotin (BV) combined with adriamycin, vinblastine, and dacarbazine (BV-AVD), with full omission of bleomycin. Treatment complications included peripheral neuropathy resulting in BV dose reduction and vinblastine discontinuation. Worsening thrombocytopenia led to discontinuation of dacarbazine. Interim imaging showed tumor regression, with post-treatment positron emission tomography with computed tomography (PET-CT) confirming complete metabolic response. Involved-site radiotherapy was omitted to minimize long-term risks of skin malignancy, local skin reactions and poor skin healing, in the context of DC. Post-treatment bone marrow evaluation showed no evidence of myeloid malignancy or lymphoma. This case demonstrates that modified BV-AVD can achieve complete metabolic remission in DC patients with cHL, while managing significant treatment-related toxicities. It underscores the critical need for individualized therapy in patients with DC and supports careful consideration of radiation omission to reduce secondary malignancy risk. These findings provide a potential therapeutic framework for managing Hodgkin lymphoma in patients with DC.
2025-12-03 | Structure-based peptide design identifies inhibitors of the dyskerin/dyskerin interaction in H/ACA ribonucleoproteins targeting brain tumour cell lines
H/ACA ribonucleoparticles (RNPs) play key regulatory roles in ribosome biogenesis, splicing, and telomerase maintenance and their activities are enhanced in cancer cells. The central component of H/ACA RNPs is the enzyme dyskerin (DKC1). DKC1 has high expression in multiple tumour types, and contributes to cancer hallmarks, tumour growth and cellular immortalization. DKC1 mutations also cause dyskeratosis congenita, a premature-ageing syndrome characterised by hindered ribosome biogenesis and shortened telomeres. We leveraged genetic information to devise a strategy to generate dyskerin inhibitors. Mapping of DKC1 mutations on the cryo-EM structures of H/ACA RNP showed they alter the dyskerin/dyskerin protein-protein interaction in this complex. Based on this, we designed and synthesised peptides that inhibit dyskerin dimerization and developed in vitro protein assays demonstrating protein engagement and interaction inhibition. Lead peptides were tested in brain tumour cells (medulloblastoma and glioblastoma) and caused alterations in cell growth, viability, apoptosis, protein synthesis and snoRNA and telomerase RNA (hTERT) levels. These results suggest for the first time that inhibition of the protein interactions within the H/ACA RNP offers a new target for cancer treatment.
2024-10-17 | Structure based peptide design to target the dyskerin dimer protein interaction of telomerase.
A hallmark of cancer is replicative immortality. In 80-90% of cancers this is due to the reactivation of telomerase, and elongation of telomeres. In patients with Dyskeratosis Congenita, a disease characterised by shortened telomeres, genetic mutations alter the dyskerin/dyskerin protein-protein interaction in the H/ACA ribonucleoprotein (RNP) module of telomerase. Based on the telomerase cryo-EM structure, we designed and synthesised linear, hydrocarbon and lactam stapled peptides that inhibit this protein interaction. We developed in vitro fluorescence and homogenous time resolved fluorescence (HTRF) assays with recombinant MBP-dyskerin demonstrating protein engagement and interaction inhibition. Lead peptides inhibit cell growth in cells that demonstrate higher levels or dyskerin, but do not affect cells with lower levels of dyskerin. These results suggest for the first time inhibition of the protein interactions within the H/ACA RNP offers a new target for broad spectrum cancer treatment.
2024-03-20 | Peptide inhibitors of the dyskerin/dyskerin protein-protein interaction, a cancer target highlighted by Dyskeratosis Congenita mutations in ribonucleoproteins of telomerase.
A hallmark of cancer is the ability to replicate limitlessly making them immortal. In 80-90% of cancer cells this is due to the reactivation of telomerase, and elongation of telomeres. In patients with Dyskeratosis Congenita, a disease characterised by shortened telomeres, genetic mutations are transcribed to the dyskerin/dyskerin protein-protein interaction in the H/ACA ribonucleoprotein (RNP) module of telomerase. Based on the telomerase cryo-EM structure, we designed and synthesised linear, hydrocarbon and lactam stapled peptides, and developed in vitro fluorescence and homogenous time resolved fluorescence (HTRF) assays with recombinant MBP-dyskerin. Lead peptides were able to bind to dyskerin, prevent the dyskerin/dyskerin interactions. They inhibit cell growth in MCF-7 cells that demonstrate above average dyskerin expression but were unable to affect A549 cells with below average dyskerin expression. Results suggest inhibition of the protein interactions within the H/ACA RNP offer a new target for broad spectrum cancer treatment.
2023-08-28 | The Molecular and Genetic Mechanisms of Inherited Bone Marrow Failure Syndromes: The Role of Inflammatory Cytokines in Their Pathogenesis.
Inherited bone marrow failure syndromes (IBMFSs) include Fanconi anemia, Diamond-Blackfan anemia, Shwachman-Diamond syndrome, dyskeratosis congenita, severe congenital neutropenia, and other rare entities such as GATA2 deficiency and SAMD9/9L mutations. The IBMFS monogenic disorders were first recognized by their phenotype. Exome sequencing has validated their classification, with clusters of gene mutations affecting DNA damage response (Fanconi anemia), ribosome structure (Diamond-Blackfan anemia), ribosome assembly (Shwachman-Diamond syndrome), or telomere maintenance/stability (dyskeratosis congenita). The pathogenetic mechanisms of IBMFSs remain to be characterized fully, but an overarching hypothesis states that different stresses elicit TP53-dependent growth arrest and apoptosis of hematopoietic stem, progenitor, and precursor cells. Here, we review the IBMFSs and propose a role for pro-inflammatory cytokines, such as TGF-β, IL-1β, and IFN-α, in mediating the cytopenias. We suggest a pathogenic role for cytokines in the transformation to myeloid neoplasia and hypothesize a role for anti-inflammatory therapies.
small molecules
2026-07-17 | Telomere and Aging Why Your Chromosome Has Shoelace TipsTelomeres—the repetitive nucleoprotein caps at the ends of linear chromosomes—function as protective "aglets" that prevent genomic instability and progressive DNA loss. This review synthesizes four decades of telomere research, from the discovery of the end‑replication problem to the latest insights into shelterin dynamics, telomerase regulation, and the non‑linear shortening of telomeres across the human lifespan. We critically examine the mechanistic links between telomere attrition, cellular senescence, oxidative stress, and mitochondrial dysfunction, and evaluate the evidence that positions telomere length as both a biomarker and a potential driver of biological aging. The clinical relevance of telomere biology is illustrated through disorders such as Dyskeratosis Congenita and the dual role of telomerase in cancer. Finally, we assess emerging interventions—from lifestyle modification to telomerase activators and gene‑editing approaches—and highlight key methodological pitfalls in telomere length measurement. By integrating structural, molecular, epidemiological, and clinical perspectives, this review provides a balanced, evidence‑based framework for understanding telomeres as central players in the aging process.
Telomeres—the repetitive nucleoprotein caps at the ends of linear chromosomes—function as protective "aglets" that prevent genomic instability and progressive DNA loss. This review synthesizes four decades of telomere research, from the discovery of the end‑replication problem to the latest insights into shelterin dynamics, telomerase regulation, and the non‑linear shortening of telomeres across the human lifespan. We critically examine the mechanistic links between telomere attrition, cellular senescence, oxidative stress, and mitochondrial dysfunction, and evaluate the evidence that positions telomere length as both a biomarker and a potential driver of biological aging. The clinical relevance of telomere biology is illustrated through disorders such as Dyskeratosis Congenita and the dual role of telomerase in cancer. Finally, we assess emerging interventions—from lifestyle modification to telomerase activators and gene‑editing approaches—and highlight key methodological pitfalls in telomere length measurement. By integrating structural, molecular, epidemiological, and clinical perspectives, this review provides a balanced, evidence‑based framework for understanding telomeres as central players in the aging process.
2026-06-02 | The R2T(P) complex orchestrates the SHQ1 driven early steps of box H/ACA snoRNP maturation
Abstract The chaperones RuvBL1 and RuvBL2 are members of the AAA+ ATPase family and participate in diverse cellular processes, including DNA repair, transcriptional regulation, and assembly of macromolecular complexes such as snoRNPs. The biogenesis of box H/ACA snoRNPs additionally requires the assembly factor SHQ1. These protein-RNA complexes are essential for ribosome biogenesis and telomerase stability and are linked to diseases such as dyskeratosis congenita and cancer. Despite detailed knowledge of mature complexes, their assembly mechanisms and how they can be modulated remain unclear. We characterize a trimeric interaction between SHQ1 and RuvBL1:RuvBL2, providing insight into early maturation of the protein-only precursor of box H/ACA snoRNPs. SHQ1 binds the flexible domain II of RuvBL1:RuvBL2, corresponding to the dodecamerization interface, suggesting disruption of this interface and promotion of hexamer formation. We further purified a complex containing RuvBL1:RuvBL2, SHQ1, and DKC1, the catalytic component of H/ACA snoRNPs and a client of SHQ1. This demonstrates that SHQ1 and DKC1 can simultaneously associate with RuvBL1:RuvBL2, potentially facilitating DKC1 release and subsequent snoRNA binding. Additionally, we identified a direct interaction between SHQ1 and RPAP3, a co-chaperone of RuvBL1:RuvBL2 (within the R2TP). Hence, RPAP3 may be responsible for recruiting SHQ1:DKC1 to hexameric RuvBL1:RuvBL2 and/or assist in the AAA+ mediated dissociation of the dimer. Since SHQ1 shares a domain with PIH1D1, an integral member of the R2TP complex, our findings suggest that early H/ACA snoRNP maturation may involve the R2T instead of the previously proposed R2TP complex.
2026-04-25 | Mathematical modelling of premature haematopoietic ageing in dyskeratosis congenita.
Idiopathic dyskeratosis congenita (DC) is a disorder characterized by mucocutaneous alterations, bone-marrow failure, immune deficiency, liver cirrhosis, and other morbidities, due to alterations in telomere maintenance, which, in most cases, lead to short telomeres and poor tissue regeneration and function. The main cause of mortality is bone-marrow failure. A non-local diffusion-advection model with zero-flux boundary conditions is used to simulate the generational and temporal evolution of a hematopoietic stem cell (HSC) population in order to investigate the progression of DC. Blood-cell production from progenitor cells that had exited the HSC compartment was quantified. The influence of variations in initial proliferation potential ([Formula: see text]) and telomerase activity (s) on the onset of pancytopenia was examined. Age-and weight-dependent blood cell demands are modeled for both sexes, establishing a physiological baseline against which DC-related deficiencies are compared. Simulations revealed that lower [Formula: see text] values and reduced telomerase activity accelerate stem cell exhaustion, resulting in early pancytopenia, sometimes before age of 2 years. In contrast, patients with moderately higher [Formula: see text] values developed pancytopenia later in life, with onset delayed until the third or fourth decade. Treatment simulations demonstrated that a two-year course of danazol, a synthetic androgen, can slow telomere attrition. These findings suggest that pharmacological intervention may delay hematopoietic failure and possibly improve the production of oocytes with better-preserved telomeres in female DC patients. Our model provides a valuable framework for assessing (or understanding, or both) disease progression and evaluating therapeutic strategies in telomeropathy-associated bone marrow failure.
2026-03-29 | Bone marrow failure in telomere biology disorders: Current understanding and the emerging landscape of non-transplant therapies.
Telomere biology disorders (TBDs) are a heterogeneous group of inherited systemic diseases caused by pathogenic variants in genes encoding telomerase or proteins involved in telomere maintenance or protection. With very short and/or dysfunctional telomeres, patients with TBD have clinical manifestations clustered in tissues with high rates of cell proliferation. Bone marrow failure (BMF) is the most common hematologic complication of a TBD and can precede the development of more difficult-to-treat malignant transformation. However, not all patients with TBD develop BMF, and some genotype/phenotype correlations are emerging. While allogeneic hematopoietic cell transplant (HCT) is curative for BMF in TBD, toxicities of the conditioning regimen can be detrimental to other organs. Balancing the risk of malignant transformation with HCT toxicity is a core challenge for providers who care for patients with TBD-associated BMF. Herein, we review the clinical presentation, pathophysiology, surveillance, and non-HCT treatment of BMF in TBD, including supportive care, androgens, thrombopoietin receptor agonists, and investigational approaches.
2026-01-07 | A rare case of dyskeratosis congenita with DKC1 mutation presenting initially as thrombocytopenia: Case report.
Dyskeratosis congenita is a rare genetic disorder classically characterized by the mucocutaneous triad and bone marrow failure. Diagnosis is challenging when hematologic manifestations precede classic features. A 10-year-old male initially presented with isolated thrombocytopenia, which was misdiagnosed as aplastic anemia. Retrospective examination revealed the mucocutaneous triad. Genetic testing confirmed a pathogenic hemizygous DKC1 mutation (c.1058C>T, p.A353V). The patient received a 3-month course of androgen therapy. Genetic counseling and prenatal testing were conducted for the family. Androgen therapy maintained platelets at 30-60 × 109/L without bleeding or adverse events during follow-up. The asymptomatic mother was a heterozygous carrier. Prenatal testing identified the same mutation in a male fetus, leading to pregnancy termination at 24 weeks. Dyskeratosis congenita can present with isolated cytopenia, risking misdiagnosis. Early genetic confirmation is vital for management and enables informed reproductive planning through prenatal diagnosis. Androgen therapy may be an effective supportive treatment.
cell therapies
2026-01-01 | Umbilical Cord Blood Transplantation for Patients with Idiopathic and Inherited Bone Marrow Failure Disorders
Abstract Umbilical cord blood transplantation (UCBT) offers a viable hematopoietic stem cell source for patients with idiopathic and inherited bone marrow failure (BMF) syndromes lacking matched related donors (MRDs) or matched unrelated donors (MUDs). Although its use has declined with the rise of haploidentical transplantation, UCBT remains crucial for select patients, especially children. The approach is associated with rapid donor availability, low graft versus host disease (GvHD) risk, and favorable outcomes in matched settings. Retrospective data and prospective trials demonstrate encouraging survival, particularly with appropriate cell dose, minimal human leukocyte antigen (HLA) mismatch, and fludarabine (Flu)-based reduced-intensity conditioning (RIC) regimens. Specific syndromes such as Fanconi anemia (FA), severe aplastic anemia (SAA), dyskeratosis congenita (DC), and Diamond–Blackfan anemia (DBA) highlight distinct challenges and considerations in UCBT application. While matched sibling UCBT shows excellent outcomes, unrelated UCBT requires careful patient selection and transplant expertise. As research advances and transplant protocols evolve, UCBT remains a critical option in the curative landscape for patients with BMF syndromes.
2025-10-18 | Hematopoietic cell transplantation in inherited bone marrow failure syndromes
Inherited bone marrow failure syndromes (IBMFS) comprise a heterogeneous group of rare genetic disorders characterized by defective hematopoiesis, congenital anomalies, and a predisposition to clonal evolution and malignancies. Hematopoietic cell transplantation remains the only curative option for the hematologic manifestations of these disorders, although it does not correct congenital malformations or eliminate the long-term risk of non-hematopoietic cancers. This review summarized current evidence and transplantation strategies for major IBMFS, including Fanconi anemia, dyskeratosis congenita/telomere biology disorders, Diamond-Blackfan anemia, Shwachman-Diamond syndrome, congenital neutropenia, congenital amegakaryocytic thrombocytopenia, and other inherited thrombocytopenias. We discussed disease-specific transplant indications, donor selection, conditioning regimens, graft source preferences, and outcomes across different patient populations. Advances in reduced-intensity conditioning and post-transplant cyclophosphamide have expanded donor availability, improving survival even with alternative donors. Nevertheless, long-term challenges persist, such as increased risks of solid tumors, endocrine dysfunction, and organ toxicity, emphasizing the need for multidisciplinary care and lifelong surveillance. Optimal outcomes depend on timely referral to specialized centers, meticulous donor screening, and individualized transplant strategies tailored to the unique biology of each disorder.
2025-07-08 | Telomere Biology Disorder Predisposition in Bone Marrow Failure and Clonal Hematopoiesis
Abstract Telomere biology disorders (TBDs), exemplified by dyskeratosis congenita (DC), are characterized by genetic defects in telomere maintenance genes, leading to telomere attrition and multi-organ manifestations including bone marrow failure (BMF) and increased malignancy risk. This study aimed to evaluate the prevalence and clinical impact of rare possibly significant variations (PSVs) in telomere-related genes among patients with BMF and clonal hematopoiesis disorders. We analyzed 1320 patients diagnosed with aplastic anemia, myelodysplastic syndrome, acute myeloid leukemia, or acute lymphoblastic leukemia and identified 113 PSVs in 103 patients, significantly exceeding the prevalence in the general population (gnomAD). The most frequently mutated genes were RTEL1 (37%) and CTC1 (30%). While missense variants predominated, novel variants accounted for approximately 27.4%. Patients harboring PSVs exhibited significantly shorter telomeres compared to unaffected relatives, reinforcing telomere length as a critical functional biomarker. Telomere-mediated genetic anticipation was clearly evident: younger patients had notably shorter telomeres compared to their older first-degree relatives, reflecting cumulative generational telomere attrition and progressively severe phenotypes. Despite variability in clinical presentations—with many patients lacking classical mucocutaneous or fibrotic manifestations—telomere shortening provided robust onset information. Our findings emphasize the importance of integrating genetic testing and telomere length measurement into clinical practice for early diagnosis, personalized risk stratification, and tailored management, including reduced-intensity conditioning transplantation and emerging targeted therapies.
2025-03-10 | Haploidentical Hematopoietic Cell Transplantation in Dyskeratosis Congenita with Myelodysplastic Syndrome/Acute Myeloid Leukemia.
Allogeneic hematopoietic cell transplantation (Allo-HCT) is the only curative option for marrow failure, myelodysplastic syndrome (MDS), and acute myeloid leukemia associated with dyskeratosis congenita (DKC). Due to chromosomal instability and sensitivity to radiation and alkylating agents, HCT is associated with a high incidence of transplant-related mortality in DKC. A 25-year-old male presented with DKC-associated cutaneous manifestations and myelodysplastic syndrome / acute myelogenous leukemia (MDS/AML). Targeted next-generation sequencing revealed mutation of the DKC1 and RUNX1 genes. His mother and sibling sisters were carriers for the DKC1 mutation. Due to high donor-specific antibody mean fluorescence intensity (DSA-MFI) against the unshared Human Leukocyte Antigen-A (HLA-A) allele of his 6/12 HLA-matched father, his paternal cousin's sister was selected as a haploidentical (6/12 HLA-matched) donor for HCT. He underwent allo-HCT with stable disease burden using a specifically-designed RIC regimen containing treosulfan (at 50% reduced dosing), fludarabine, and rabbit anti-thymocyte globulin. The graft versus host disease (GVHD) prophylaxis contained reduced-dose post-transplant cyclophosphamide (PTCy dose reduction of 50%) with mycophenolate mofetil and cyclosporine. He engrafted with complete donor chimerism, and the day +30 marrow was in complete morphological remission with undetectable measurable residual disease by flow cytometry. On day +126, he developed steroid-responsive late-onset grade II acute GVHD (stage III skin GVHD). He suffered from morphologic relapse on day +220 and succumbed from sepsis with septic shock on day +256. This case demonstrates the safety and feasibility of haploidentical-HCT using a treosulfan-based reduced-intensity conditioning (RIC) regimen and modified PTCy-based GVHD prophylaxis in DKC. Disease relapse in this patient underscores the impact of pretransplant disease burden on relapse free survival in DKC patients with MDS/AML who are not eligible for myeloablative conditioning.
2025-02-25 | Clinical Use of ZSCAN4 for Telomere Elongation in Hematopoietic Stem Cells.
Extremely short telomeres in patients with dyskeratosis congenita and related telomere biology disorders (TBDs) lead to premature cellular senescence and bone marrow failure. Zinc finger and SCAN domain-containing 4 (ZSCAN4) elongates telomeres by recombination. We report a clinical study in which EXG34217, the term given for autologous CD34+ hematopoietic stem cells from patients with TBD exposed to a temperature-sensitive Sendai virus vector encoding human ZSCAN4 at 33°C for 24 hours, was infused into patients without preconditioning. Four patients were enrolled; two experienced successful CD34+ mobilization during the second mobilization attempt and underwent apheresis and EXG34217 infusion, with follow-up of 5 and 24 months (both ongoing). We observed telomere elongation (1.06- to 1.34-fold) in CD34+ cells ex vivo. In one patient, the treatment was associated with a change in the mean absolute neutrophil count (ANC) from 1.78×103 to 3.18×103 cells/μl; the lymphocyte subpopulation telomere length changed from 3.6 to 6.7 kb (50th percentile for age). In the other patient, the treatment was associated with a change in the lowest ANC from 0.6×103/μl to 1.2×103/μl; this has occurred in 5 months without the patient receiving prior intermittent low-dose granulocyte-colony-stimulating factor injections. During mobilization, all patients experienced mild to moderate bone pain or pain after line replacement, and one patient had a blood infection associated with fever and hypoxemia. After EXG34217 infusion, no acute safety issues were noted; in one patient mild to moderate long-term cardiac and pulmonary adverse events were noted; these were similar to symptoms of the patient's underlying conditions. Although definitive conclusions cannot be drawn from the two EXG34217-treated patients, these results warrant further investigation of CD34+ cells exposed to ZSCAN4 for treating TBDs. (Funded by Elixirgen Therapeutics; ClinicalTrials.gov number, NCT04211714.).
gene therapies
2026-08-07 | The potential of gene therapy to rescue telomeric and extratelomeric defects in X-linked dyskeratosis congenita.
Dyskeratosis congenita (DC) is a rare inherited disorder characterized by bone marrow failure, pulmonary fibrosis, and cancer predisposition. X-linked DC (X-DC) is caused by mutations in the DKC1 gene, which encodes dyskerin, a multifunctional protein that is essential for telomere maintenance and multiple RNA-associated processes. Here, we first generated human X-DC HSPC models by introducing DKC1 frameshift mutations or the hypomorphic c.196 A>G mutation, into cord blood CD34+ cells from healthy male donors. These X-DC-like HSPCs recapitulated key hematopoietic features of the disease, including impaired proliferation, defective telomere maintenance and altered rRNA maturation. To correct these defects, lentiviral vectors were constructed carrying DKC1 under the PGK promoter or a weaker promoter driven by TERC regulatory sequences. While PGK-driven expression of dyskerin only restored the proliferation of X-DC-like HSPCs, pTERC-mediated expression of dyskerin also corrected the telomere maintenance and rRNA maturation defects characteristic of X-DC cells, without altering the functional properties of healthy HSPCs. These findings indicate that TERC promoter-driven dyskerin expression can functionally rescue key telomeric and extratelomeric defects in HSPCs carrying frameshift or hypomorphic DKC1 mutations, supporting further preclinical development of this strategy and providing a rationale for its evaluation as a therapeutic approach for X-linked dyskeratosis congenita.
2026-05-01 | C29-13 Somatic Variants Rescue Bone Marrow Failure, But Not Lung Disease in Patients With Germline Variants in TINF2
Abstract Introduction Telomeres are essential for genome maintenance. Rare variants disrupting telomere maintenance genes cause a spectrum of short telomere syndromes, with idiopathic pulmonary fibrosis (IPF) as the most common phenotype. Variants in the shelterin component TIN2 typically cause severe pediatric dyskeratosis congenita (DC) and bone marrow failure. However, a subset of patients with germline TINF2 variants presents with less severe, adult-onset disease, including IPF, suggesting the presence of modifying factors. Methods We identified three patients with pathogenic germline TINF2 hotspot variants evaluated at the University of Pittsburgh Medical Center for lung transplantation. Two had a family history of DC; one had a sporadic presentation. Clinical genetic testing and deep exome sequencing was used to identify somatic variants. We validated the function of somatic variants in vitro using CRISPR/Cas9-mediated genome editing in multiple cell lines and in patient-derived induced pluripotent stem cells (iPSCs). Results All three patients had somatic variants in the DNA-binding domain of POT1 where tumor-specific variants have been previously reported. Edited cells showed no signs of DNA damage, genomic instability, or altered growth kinetics. Telomeres progressively lengthened in all edited lines. iPSCs reprogrammed from patient PBMCs, which harbored both the germline TINF2 and somatic POT1 variants, also demonstrated gradual telomere lengthening, verifying the POT1 variants are functional and sufficient for telomere elongation, even in the context of the pathogenic TINF2 variant. Conclusions Somatic POT1 variants appear to rescue hematopoietic function and cause telomere lengthening in vitro. POT1 editing is efficient and does not appear to influence genome stability. We propose that genetically modifying POT1 may be an effective therapy to rescue the bone marrow of patients with short telomeres. This abstract is funded by: NA
2026-01-02 | Oral squamous cell carcinoma risk and magnitude of association in inherited cancer predisposition syndromes: evidence from a large real-world cohort.
Inherited cancer predisposition syndromes (ICPS) are rare genetic disorders associated with an elevated cancer risk. This study evaluates oral squamous cell carcinoma (OSCC) prevalence across selected ICPS, including Fanconi anemia (FA), Plummer-Vinson syndrome, Cowden syndrome, Li-Fraumeni syndrome, dyskeratosis congenita, and xeroderma pigmentosum, quantifies risk magnitude, examines age at diagnosis, and assesses tobacco's modifying effect on OSCC risk in these populations. We conducted a retrospective cohort study using the TriNetX Research Network, including patients with or without ICPS identified by ICD‑10 codes over a 20‑year period. OSCC cases were matched 1:1 by age and sex to controls. The analyses assessed prevalence, odds ratios, age at diagnosis, and the impact of tobacco use. Statistical significance was set at P < .05. The prevalence of OSCC among ICPS patients ranged from 0.11% to 4.66%, with the highest in patients with FA. Among ICPS, only FA showed a markedly increased OSCC risk (OR = 40.63, P < .01), while Plummer-Vinson syndrome and dyskeratosis congenita were inversely associated. Patients with ICPS developed OSCC at younger ages (P < .0001). Smoking increased OSCC risk within ICPS (OR = 1.47), whereas nonsmokers with ICPS had a reduced risk (OR = 0.78). FA is strongly associated with OSCC; OSCC also occurs in Li-Fraumeni syndrome and Cowden syndrome. Patients with ICPS present with OSCC at a younger age, supporting targeted screening for high‑risk ICPS populations.
2025-12-10 | Fueling for the finish line: Control of human telomerase activity by nucleotide metabolism.
Telomeres are repetitive DNA sequences that preserve genome integrity. Human telomere length is kept in a tight window through a balance between telomere erosion during genome replication and telomere elongation by the telomerase reverse transcriptase. In humans, genetically determined telomere length is associated with lifespan, while inherited defects in telomere length maintenance genes predispose to a spectrum of lethal diseases termed telomere biology disorders (TBDs). Recently, dNTP metabolism has emerged as a previously underappreciated pathway that is critical for human telomerase regulation and telomere length control. Genome-wide association studies have implicated variation in several dNTP metabolism genes with human telomere length. Genetic variants at the TYMS locus, which encodes the rate limiting thymidine synthesis enzyme thymidylate synthase, have been shown to cause the TBD dyskeratosis congenita. Genome-wide CRISPR/Cas9 functional screening has linked telomere length control to multiple key dNTP metabolism genes. Remarkably, mechanistic studies emerging from these genetic data have revealed a profound, bidirectional sensitivity of human telomerase activity to cellular dNTP levels, that is readily manipulated through several metabolic control nodes. Here, we review the emerging genetic evidence and mechanistic studies supporting the relationship between dNTP metabolism and telomere length control. We present an integrated model for human telomerase regulation, wherein the levels of dNTP substrates govern telomerase reverse transcriptase activity and in turn human telomere length. We discuss the therapeutic prospects and recent trials for manipulating dNTP metabolism to treat TBDs and related degenerative diseases.
2025-12-03 | CRISPR–Cas9 mediated gene therapy in inherited bone marrow failure syndromes
Introduction This systematic review evaluates CRISPR–Cas9 mediated gene therapy for inherited bone marrow failure syndromes, a heterogeneous group of rare inherited disorders characterised by cytopenia, cancer predisposition, and multi-organ involvement, for which supportive care and allogeneic haematopoietic stem cell transplantation provide cures for some but remain imperfect, donor-limited, and associated with significant morbidity. The objective of this review is to evaluate the current state of CRISPR–Cas9 mediated gene therapy in inherited bone marrow failure syndromes, with a focus on how this technology has been applied in experimental models to correct pathogenic mutations and restore haematopoietic function. Methods We searched PubMed, Scopus, and Google Scholar for studies combining inherited bone marrow failure syndromes with gene editing, prime editing, base editing, or CRISPR–Cas9. Results Of 876 records screened, 18 met the inclusion criteria. Fanconi anaemia predominated (n=8), with additional work in severe congenital neutropenia (n=3), Shwachman–Diamond syndrome (n=2), Diamond–Blackfan anaemia (n=2), and single studies in dyskeratosis congenita, congenital amegakaryocytic thrombocytopenia, and myelodysplastic syndrome/ acute myeloid leukaemia predisposition. Discussion Overall, CRISPR–Cas9 has demonstrated feasibility for ex vivo correction in inherited bone marrow failure syndromes; however, future clinical adaptation will depend on overcoming key hurdles, such as careful assessment of off-target effects and establishing regulatory pathways that enable access for patients with rare diseases, thereby bridging the gap between preclinical and therapeutic application.
oligonucleotides
2023-10-02 | LARP3, LARP7, and MePCE are Involved in the Early Stage of Human Telomerase RNA Biogenesis
Human telomerase assembly is a highly dynamic process. Using biochemical approaches, we found that LARP3 and LARP7/MePCE are involved in the early stage and that their binding to hTR is destabilized when the mature hTR is produced. LARP7 and MePCE knockdown inhibits the conversion of the 3′-extended short (exS) form into mature hTR and the cytoplasmic accumulation of hTR, resulting in telomere shortening. LARP3 plays a negative role in preventing the processing of the 3′-extended long (exL) form and binding of LARP7 and MePCE. Interestingly, the tertiary structure of the exL form prevents LARP3 binding and facilitates hTR biogenesis. Supporting this process, LARP3 at low levels promotes hTR maturation, increases telomerase activity, and elongates telomeres. Our data suggest that LARP3 and LARP7/MePCE mediate the processing of hTR precursors and thus control the production of functional telomerase.
2023-09-22 | Telomerase RNA-based aptamers restore defective myelopoiesis in congenital neutropenic syndromes
Telomerase RNA (TERC) has a noncanonical function in myelopoiesis binding to a consensus DNA binding sequence and attracting RNA polymerase II (RNA Pol II), thus facilitating myeloid gene expression. The CR4/CR5 domain of TERC is known to play this role, since a mutation of this domain found in dyskeratosis congenita (DC) patients decreases its affinity for RNA Pol II, impairing its myelopoietic activity as a result. In this study, we report that two aptamers, short single-stranded oligonucleotides, based on the CR4/CR5 domain were able to increase myelopoiesis without affecting erythropoiesis in zebrafish. Mechanistically, the aptamers functioned as full terc; that is, they increased the expression of master myeloid genes, independently of endogenous terc, by interacting with RNA Pol II and with the terc-binding sequences of the regulatory regions of such genes, enforcing their transcription. Importantly, aptamers harboring the CR4/CR5 mutation that was found in DC patients failed to perform all these functions. The therapeutic potential of the aptamers for treating neutropenia was demonstrated in several preclinical models. The findings of this study have identified two potential therapeutic agents for DC and other neutropenic patients.
2023-09-17 | CRISPR screen identifies CEBPB as contributor to dyskeratosis congenita fibroblast senescence via augmented inflammatory gene response.
Abstract Aging is the consequence of intra- and extracellular events that promote cellular senescence. Dyskeratosis congenita (DC) is an example of a premature aging disorder caused by underlying telomere/telomerase-related mutations. Cells from these patients offer an opportunity to study telomere-related aging and senescence. Our previous work has found that telomere shortening stimulates DNA damage responses (DDRs) and increases reactive oxygen species (ROS), thereby promoting entry into senescence. This work also found that telomere elongation via TERT expression, the catalytic component of the telomere-elongating enzyme telomerase, or p53 shRNA could decrease ROS by disrupting this telomere–DDR–ROS pathway. To further characterize this pathway, we performed a CRISPR/Cas9 knockout screen to identify genes that extend life span in DC cells. Of the cellular clones isolated due to increased life span, 34% had a guide RNA (gRNA) targeting CEBPB, while gRNAs targeting WSB1, MED28, and p73 were observed multiple times. CEBPB is a transcription factor associated with activation of proinflammatory response genes suggesting that inflammation may be present in DC cells. The inflammatory response was investigated using RNA sequencing to compare DC and control cells. Expression of inflammatory genes was found to be significantly elevated (P < 0.0001) in addition to a key subset of these inflammation-related genes [IL1B, IL6, IL8, IL12A, CXCL1 (GROa), CXCL2 (GROb), and CXCL5]. which are regulated by CEBPB. Exogenous TERT expression led to downregulation of RNA/protein CEBPB expression and the inflammatory response genes suggesting a telomere length-dependent mechanism to regulate CEBPB. Furthermore, unlike exogenous TERT and p53 shRNA, CEBPB shRNA did not significantly decrease ROS suggesting that CEBPB's contribution in DC cells’ senescence is ROS independent. Our findings demonstrate a key role for CEBPB in engaging senescence by mobilizing an inflammatory response within DC cells.
2023-07-31 | Control of protein synthesis through mRNA pseudouridylation by dyskerin.
Posttranscriptional modifications of mRNA have emerged as regulators of gene expression. Although pseudouridylation is the most abundant, its biological role remains poorly understood. Here, we demonstrate that the pseudouridine synthase dyskerin associates with RNA polymerase II, binds to thousands of mRNAs, and is responsible for their pseudouridylation, an action that occurs in chromatin and does not appear to require a guide RNA with full complementarity. In cells lacking dyskerin, mRNA pseudouridylation is reduced, while at the same time, de novo protein synthesis is enhanced, indicating that this modification interferes with translation. Accordingly, mRNAs with fewer pseudouridines due to knockdown of dyskerin are translated more efficiently. Moreover, mRNA pseudouridylation is severely reduced in patients with dyskeratosis congenita caused by inherited mutations in the gene encoding dyskerin (i.e., DKC1). Our findings demonstrate that pseudouridylation by dyskerin modulates mRNA translatability, with important implications for both normal development and disease.
2021-03-16 | Upregulation of miR‑126 inhibits podocyte injury in sepsis via EGFL6/DKC1 signaling pathway
Sepsis‑induced cardiorenal syndrome is one of the multiple organ dysfunctions observed in sepsis. It is determined by a primary dysfunction in one organ that leads to secondary injury to another organ. Studies have shown the involvement of microRNAs (miRs) in the diagnosis and prognosis of several pathologies. However, the implication of miR‑126 in the podocyte damage associated with sepsis has not been evaluated until now. In the current study, the miR‑126 expression was downregulated in a podocyte injury model together with downregulation of nephrin expression. The transfection of podocytes from podocyte injury group with miR‑126 mimics demonstrated an increase in cell proliferation and a decrease in cell apoptosis. Bioinformatics analysis predicted that the target of miR‑126 was epidermal growth factor‑like domain multiple 6 (EGFL6) and dyskeratosis congenita 1 (DKC1) and these were confirmed by dual‑luciferase reporter assay. miR‑126 upregulation determined EGFL6 and DKC1 upregulation and prevented podocyte injury. The current study demonstrated that overexpression of miR‑126 could protect podocytes from sepsis‑induced injury through an EGFL6/DKC1 signaling pathway.
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2026-04-15 | Adriamycin, Vinblastine and Dacarbazine With Immunotherapy Achieves Complete Metabolic Response in a Patient With Classical Hodgkin Lymphoma and Dyskeratosis Congenita.
Dyskeratosis congenita (DC) is a rare inherited telomeropathy characterized by defective telomere maintenance and an elevated risk of hematologic malignancies. Classical Hodgkin lymphoma (cHL) is a rare malignancy described in patients with DC, and optimal treatment remains undefined due to overlapping toxicities of standard ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) and radiation therapy in this high-risk population. We present a 48-year-old man with longstanding thrombocytopenia who was diagnosed with DC based on clinical features and genetic testing. Two years post diagnosis, he developed stage IIA bulky cHL (nodular sclerosing, CD30+, Epstein-Barr virus (EBV)+). To mitigate pulmonary and myelotoxicity risks, he received a modified regimen of brentuximab vedotin (BV) combined with adriamycin, vinblastine, and dacarbazine (BV-AVD), with full omission of bleomycin. Treatment complications included peripheral neuropathy resulting in BV dose reduction and vinblastine discontinuation. Worsening thrombocytopenia led to discontinuation of dacarbazine. Interim imaging showed tumor regression, with post-treatment positron emission tomography with computed tomography (PET-CT) confirming complete metabolic response. Involved-site radiotherapy was omitted to minimize long-term risks of skin malignancy, local skin reactions and poor skin healing, in the context of DC. Post-treatment bone marrow evaluation showed no evidence of myeloid malignancy or lymphoma. This case demonstrates that modified BV-AVD can achieve complete metabolic remission in DC patients with cHL, while managing significant treatment-related toxicities. It underscores the critical need for individualized therapy in patients with DC and supports careful consideration of radiation omission to reduce secondary malignancy risk. These findings provide a potential therapeutic framework for managing Hodgkin lymphoma in patients with DC.
2025-12-03 | Structure-based peptide design identifies inhibitors of the dyskerin/dyskerin interaction in H/ACA ribonucleoproteins targeting brain tumour cell lines
H/ACA ribonucleoparticles (RNPs) play key regulatory roles in ribosome biogenesis, splicing, and telomerase maintenance and their activities are enhanced in cancer cells. The central component of H/ACA RNPs is the enzyme dyskerin (DKC1). DKC1 has high expression in multiple tumour types, and contributes to cancer hallmarks, tumour growth and cellular immortalization. DKC1 mutations also cause dyskeratosis congenita, a premature-ageing syndrome characterised by hindered ribosome biogenesis and shortened telomeres. We leveraged genetic information to devise a strategy to generate dyskerin inhibitors. Mapping of DKC1 mutations on the cryo-EM structures of H/ACA RNP showed they alter the dyskerin/dyskerin protein-protein interaction in this complex. Based on this, we designed and synthesised peptides that inhibit dyskerin dimerization and developed in vitro protein assays demonstrating protein engagement and interaction inhibition. Lead peptides were tested in brain tumour cells (medulloblastoma and glioblastoma) and caused alterations in cell growth, viability, apoptosis, protein synthesis and snoRNA and telomerase RNA (hTERT) levels. These results suggest for the first time that inhibition of the protein interactions within the H/ACA RNP offers a new target for cancer treatment.
2024-10-17 | Structure based peptide design to target the dyskerin dimer protein interaction of telomerase.
A hallmark of cancer is replicative immortality. In 80-90% of cancers this is due to the reactivation of telomerase, and elongation of telomeres. In patients with Dyskeratosis Congenita, a disease characterised by shortened telomeres, genetic mutations alter the dyskerin/dyskerin protein-protein interaction in the H/ACA ribonucleoprotein (RNP) module of telomerase. Based on the telomerase cryo-EM structure, we designed and synthesised linear, hydrocarbon and lactam stapled peptides that inhibit this protein interaction. We developed in vitro fluorescence and homogenous time resolved fluorescence (HTRF) assays with recombinant MBP-dyskerin demonstrating protein engagement and interaction inhibition. Lead peptides inhibit cell growth in cells that demonstrate higher levels or dyskerin, but do not affect cells with lower levels of dyskerin. These results suggest for the first time inhibition of the protein interactions within the H/ACA RNP offers a new target for broad spectrum cancer treatment.
2024-03-20 | Peptide inhibitors of the dyskerin/dyskerin protein-protein interaction, a cancer target highlighted by Dyskeratosis Congenita mutations in ribonucleoproteins of telomerase.
A hallmark of cancer is the ability to replicate limitlessly making them immortal. In 80-90% of cancer cells this is due to the reactivation of telomerase, and elongation of telomeres. In patients with Dyskeratosis Congenita, a disease characterised by shortened telomeres, genetic mutations are transcribed to the dyskerin/dyskerin protein-protein interaction in the H/ACA ribonucleoprotein (RNP) module of telomerase. Based on the telomerase cryo-EM structure, we designed and synthesised linear, hydrocarbon and lactam stapled peptides, and developed in vitro fluorescence and homogenous time resolved fluorescence (HTRF) assays with recombinant MBP-dyskerin. Lead peptides were able to bind to dyskerin, prevent the dyskerin/dyskerin interactions. They inhibit cell growth in MCF-7 cells that demonstrate above average dyskerin expression but were unable to affect A549 cells with below average dyskerin expression. Results suggest inhibition of the protein interactions within the H/ACA RNP offer a new target for broad spectrum cancer treatment.
2023-08-28 | The Molecular and Genetic Mechanisms of Inherited Bone Marrow Failure Syndromes: The Role of Inflammatory Cytokines in Their Pathogenesis.
Inherited bone marrow failure syndromes (IBMFSs) include Fanconi anemia, Diamond-Blackfan anemia, Shwachman-Diamond syndrome, dyskeratosis congenita, severe congenital neutropenia, and other rare entities such as GATA2 deficiency and SAMD9/9L mutations. The IBMFS monogenic disorders were first recognized by their phenotype. Exome sequencing has validated their classification, with clusters of gene mutations affecting DNA damage response (Fanconi anemia), ribosome structure (Diamond-Blackfan anemia), ribosome assembly (Shwachman-Diamond syndrome), or telomere maintenance/stability (dyskeratosis congenita). The pathogenetic mechanisms of IBMFSs remain to be characterized fully, but an overarching hypothesis states that different stresses elicit TP53-dependent growth arrest and apoptosis of hematopoietic stem, progenitor, and precursor cells. Here, we review the IBMFSs and propose a role for pro-inflammatory cytokines, such as TGF-β, IL-1β, and IFN-α, in mediating the cytopenias. We suggest a pathogenic role for cytokines in the transformation to myeloid neoplasia and hypothesize a role for anti-inflammatory therapies.
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Drug Discovery Landscape
2 orphan drug designations for Dyskeratosis congenita.
2 orphan drug designations for Dyskeratosis congenita.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
autologous CD34+ cells contacted ex vivo with EXG-001 Sendai virus vector | gene therapies | FDA | Elixirgen Therapeutics, Inc. | |
Recombinant human dyskerin | proteins | EMA | — | Advanced Medical Projects |
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