RARE DISEASE
Ataxia-telangiectasia
Ataxia-telangiectasia
Ataxia-telangiectasia
Synonyms: Louis-Bar syndrome
Synonyms: Louis-Bar syndrome
Synonyms: Louis-Bar syndrome
Drug discovery
8
drugs
With orphan designations
Overview
Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder caused by ATM gene mutations, impairing DNA repair and cell cycle regulation. It manifests with progressive cerebellar degeneration (onset <5 years), oculocutaneous telangiectasias, combined immunodeficiency, and cancer predisposition. Key features include ataxia, oculomotor apraxia, recurrent sinopulmonary infections, and hypersensitivity to ionizing radiation. Neurological decline typically necessitates wheelchair use by adolescence, with mortality driven by malignancy (35% by age 20) or respiratory failure [1][4][6][12].
Burden
Mortality: Median survival 14–25 years; malignancy (leukemia/lymphoma) and respiratory failure dominate [4][6][12]
Morbidity: Progressive neurodegeneration, immunodeficiency-related infections, insulin resistance, and pulmonary fibrosis [4][7][8]
Quality of life: ≥80% wheelchair-dependent by adolescence; high care needs and psychosocial impact on families [4][5][12]
Therapies
Supportive care: Physical/speech therapy, immunoglobulin replacement, prophylactic antibiotics [6][16]
Symptomatic management: Antioxidants (e.g., vitamin E), beta-blockers for tremor, chest physiotherapy [3][8][16]
Experimental approaches: Erythrocyte-delivered dexamethasone, ASO therapy, and nicotinamide riboside in clinical trials [8][13][16]
Categories: rare developmental anomalies during embryogenesis, rare endocrine diseases, rare genetic diseases, rare gynecological and obstetric diseases, rare immunological diseases, rare neoplastic diseases, rare neurological diseases, rare ophthalmic disorders, rare skin diseases, rare transplant-related disorders
Research Papers
1,734 drug discovery papers about Ataxia-telangiectasia, with 3 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,734 drug discovery papers about Ataxia-telangiectasia, with 3 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-17 | Emerging roles of ATR beyond DNA damage repair: orchestrating transcriptional reprogramming during epithelial-to-mesenchymal transition.
The ability of cancer cells to transition between epithelial and mesenchymal states, a process known as epithelial-to-mesenchymal transition (EMT), is a key driver of cancer metastasis and therapy resistance. While ataxia telangiectasia and Rad3-related (ATR) kinase was originally characterized as a responder to DNA damage and replication stress, recent discoveries implicate a critical role for ATR in EMT and metastasis. Two pivotal studies published in this issue of JCI provide key insights into how ATR intersects with EMT transcriptional reprogramming. Patel et al. demonstrated that ATR prevented R-loop accumulation at EMT-related gene loci, thereby facilitating the transcriptional reprogramming necessary for EMT as well as tumor growth and metastasis. Tu et al. further uncovered a role for ATR in ECM stiffness-induced EMT, which was associated with an immunosuppressive tumor microenvironment. Together, these studies highlight important therapeutic implications for ATR targeting in the context of metastasis and therapy resistance.
2026-07-31 | Exploiting the weak link: Ataxia-Telangiectasia Mutated dysfunction in oesophagogastric tumours.
ATM (ataxia-telangiectasia mutated) is a central regulator of the DNA damage response, coordinating double-strand break repair, checkpoint control, and cell fate decisions. Its disruption drives genomic instability and has been implicated across multiple tumour types. In oesophagogastric cancers, ATM alterations occur in a clinically relevant subset of cases, encompassing both somatic and germline events, and are associated with distinct molecular features including reduced co-occurrence with TP53 mutations and elevated homologous recombination deficiency scores. This narrative review synthesises published literature and publicly available genomic databases to examine ATM biology, the spectrum of ATM alterations across oesophageal adenocarcinoma, oesophageal squamous cell carcinoma, and gastric cancer subtypes, and the challenges of defining true ATM deficiency. The therapeutic implications of ATM dysfunction are evaluated across radiotherapy, platinum-based chemotherapy, ATR inhibition, and PARP inhibition. ATM alterations are detected in approximately 6% of tumours pan-cancer and in up to 10% of oesophagogastric cases. Defining ATM deficiency remains challenging, as immunohistochemistry, next-generation sequencing, and functional assays each carry distinct limitations. ATR inhibition emerges as the most consistently supported therapeutic strategy, with converging preclinical and early clinical evidence across oesophagogastric models. By contrast, available data do not support treating ATM deficiency as equivalent to BRCA-like homologous recombination deficiency, and PARP inhibitor monotherapy has not demonstrated consistent benefit. Prospective validation of functional ATM assays, histology-stratified trial design, and integration of genomic, protein-level, and functional evidence represent key priorities for translating ATM-guided strategies into oesophagogastric cancer practice.
2026-07-28 | Spatiotemporal regulation of DNA repair proteins between Golgi and nucleus maintains genome stability.
The Golgi complex serves as a critical hub for cellular homeostasis, yet its communication with the nucleus remains largely unexplored. By analyzing and siRNA-validating localization data from the Human Protein Atlas, we uncovered substantial proteome interconnectivity between the Golgi and nucleus, including an unexpected enrichment for DNA repair factors. We identify a cluster of DNA damage response (DDR) proteins occupying distinct sub-Golgi compartments that redistribute dynamically between the Golgi and nucleus in response to genotoxic stress, with the type of DNA lesion shaping the direction of redistribution. Focusing on the homologous recombination (HR) regulator RAD51C, we show that DNA damage triggers ataxia telangiectasia mutated (ATM)-dependent release of a giantin-tethered Golgi RAD51C pool, with subsequent importin-β-dependent nuclear import, where repair-associated foci form. Giantin depletion prematurely releases RAD51C, producing aberrant nuclear foci lacking key DDR markers, reducing ATM activation and HR efficiency, elevating genome instability, and accelerating proliferation. The Golgi thus acts as a spatiotemporal coordination node for DDR factors safeguarding genomic stability.
2026-07-22 | MPT0E028, a pan-HDAC inhibitor, ameliorates bleomycin-induced pulmonary fibrosis by promoting AT2-to-AT1 differentiation through the ATM/AMPK/FoxO1 pathway.
Persistent injury and impaired regeneration of the alveolar epithelium are key contributors to the pathogenesis of pulmonary fibrosis. In idiopathic pulmonary fibrosis (IPF), type 2 alveolar epithelial (AT2) cells fail to fully differentiate into type 1 alveolar epithelial (AT1) cells, remaining instead in a transitional state. Histone deacetylase (HDAC) inhibitors are promising therapeutic agents for pulmonary fibrosis. Therefore, this study investigated whether MPT0E028, a pan-HDAC inhibitor, ameliorated bleomycin (BLM)-induced pulmonary fibrosis in a therapeutic model of mice by promoting AT2-to-AT1 cell differentiation. The effects of MPT0E028 on pulmonary fibrosis were assessed by evaluating the expression of fibrogenic proteins and cell markers of AT1 (T1α and aquaporin 5 [AQP5]), AT2 (surfactant protein C [SPC]) and alveolar epithelial transitional cells (Keratin 8 [KRT8]) in a therapeutic model of BLM-induced pulmonary fibrosis in mice. The role of the ataxia-telangiectasia mutated (ATM)/AMP-activated protein kinase (AMPK)/forkhead box O1 (FoxO1) signaling pathway in MPT0E028-induced T1α expression was examined in murine AT2 cells (MLE-12 cells). Administration of MPT0E028 significantly reduced fibrosis scores; suppressed the expression of connective tissue growth factor, collagen I, fibronectin, and α-smooth muscle actin; and improved lung function in the therapeutic model of BLM-induced pulmonary fibrosis in mice. MPT0E028 enhanced the expression of T1α and AQP5 but reduced the expression of SPC and KRT8 in lung tissues from BLM-treated mice. In MLE-12 cells and primary human AT2 cells, MPT0E028 upregulated T1α and AQP5 expression in a time-dependent manner, with this accompanied by a decrease in SPC expression. AS1842856, an FoxO1 inhibitor, and FoxO1 siRNA transfection inhibited MPT0E028-stimulated T1α expression, whereas transfection with FoxO3 siRNA had no effect. FoxO1 siRNA transfection also inhibited MPT0E028-stimulated T1α-luciferase activity. MPT0E028 induced FoxO1 serine phosphorylation, increased FoxO1 recruitment to the T1α promoter, and enhanced FoxO1-luciferase activity. Compound C, an AMPK inhibitor, and AMPK siRNA transfection suppressed MPT0E028-stimulated T1α expression, and compound C also inhibited MPT0E028-promoted FoxO1 recruitment to the T1α promoter. MPT0E028 induced AMPK phosphorylation in a time-dependent manner and increased ATM acetylation and phosphorylation in MLE-12 cells. ATM siRNA transfection suppressed MPT0E028-induced T1α expression, AMPK and FoxO1 serine phosphorylation, FoxO1 recruitment to the T1α promoter, and FoxO1-luciferase activity. MPT0E028 induced FoxO1 phosphorylation in AT2 cells in the therapeutic model of BLM-induced pulmonary fibrosis in mice. MPT0E028 is the first pan-HDAC inhibitor shown to activate ATM acetylation-mediated AMPK/FoxO1 signaling to induce AT2-to-AT1 differentiation in a therapeutic model of BLM-induced pulmonary fibrosis in mice. Administration of MPT0E028 after BLM challenge effectively ameliorated pulmonary fibrosis by suppressing fibrogenic protein expression and promoting AT2-to-AT1 cell differentiation. These results suggest that MPT0E028 holds potential as a therapeutic agent for IPF treatment.
2026-07-17 | Identification of dual-targeting PROTACs for ataxia telangiectasia and RAD3-related and aurora kinase A as chemo-sensitizers for leukemia cells.
The ataxia telangiectasia and RAD3-related (ATR) kinase is a central regulator of DNA damage responses. Its pharmacological degradation by proteolysis-targeting chimeras (PROTACs) represents a promising strategy to sensitize cancer cells to DNA-damaging chemotherapy. It is currently unknown if ATR PROTACs can be pharmacologically designed to target a second cancer-relevant kinase. In this study, we report the design, synthesis, and biological evaluation of novel cereblon (CRBN)-based PROTACs for ATR. Structure-guided design and chemical synthesis enabled the development of a focused library of degraders based on selective ATR inhibitors and optimized CRBN ligands. Among the synthesized compounds, Abd141 turns out as the most promising degrader, showing potent ATR degradation in human leukemia cells, without affecting ATM, WEE1 or DNA-PKcs. Consistently, the developed PROTACs prove activity in an in vitro ATR/ATRIP binding assay. Abd141 exhibits high chemical, microsomal, and plasma stability, and no cytotoxicity in non-cancerous HEK293 cells. Proteomic studies and immunoblot experiments identify aurora kinase A (AURKA) as additional target of CRBN-induced proteasomal degradation by Abd141. Dose-degradation studies of Abd141 in the MOLT-4 cell line yielded a DC50 of 97.7 nM for ATR and 6.7 nM for AURKA. These findings disclose Abd141 as effective dual ATR/AURKA degrader and innovative chemo-sensitizer that encourages preclinical development.
proteins
2026-06-22 | A point mutation in the FAT domain constitutively increases the kinase activity of Rad3ATR and bypasses the requirement for 9-1-1 phosphorylation to activate the DNA replication checkpoint.
Ataxia telangiectasia and Rad3-related (ATR) initiates cell cycle checkpoints to maintain genome integrity in the presence of replication stress or various forms of DNA damage. However, how ATR is activated for checkpoint initiation remains incompletely understood. The canonical model suggests that binding of an ATR-activator protein relieves the autoinhibitory PIKK regulatory domain (PRD) within the kinase domain, thereby activating ATR by granting substrate access to the catalytic centre. To better understand the checkpoint initiation mechanism, we conducted a genetic screen in fission yeast that identified a charge-reversal mutation, E1369K, in the conserved FRAP-ATM-TRRAP (FAT) domain of Rad3, the ortholog of ATR. In vitro kinase assays show that the mutation converts Rad3 into a constitutively active form. This allows rescue of the Rad3 kinase signaling defect in cells lacking the phosphorylation of the Rad9-Rad1-Hus1 (9-1-1) complex specifically in the DNA replication checkpoint, not the damage checkpoint pathway. Since the mutation is not in the kinase domain and is away from the PRD, these findings show that, in addition to the canonical mechanism, Rad3 may also be activated allosterically via the FAT domain, a mechanism likely conserved in higher eukaryotes.
2026-05-01 | The multifaceted role of ATM protein in neural stem/progenitor cell biology and neurogenesis: beyond DNA damage response.
The Ataxia Telangiectasia Mutated (ATM) protein kinase is a well recognized master regulator of the DNA damage response (DDR) and cell cycle control whose dysfunction leads to the rare neurological disorder Ataxia Telangiectasia (AT). A mounting body of evidence has revealed unequivocally that ATM relevance extends far beyond its DDR role and includes critical non-canonical functions. This minireview summarizes the current knowledge on ATM role in neural stem progenitor cell (NSPC) biology and in neurogenesis. In particular, herein we highlight how ATM is crucial for NSPC proliferation, differentiation, and survival, acting not only as a guardian of genomic integrity but also as a key orchestrator of developmental timing. Furthermore, we discuss how ATM deficiency in AT leads to dysregulated NSPC proliferation, premature neuronal maturation, and impaired quality control during neurogenesis, potentially contributing to progressive neurodegeneration and complex neurological symptoms associated with this pediatric disorder. By integrating canonical and non-canonical mechanisms, this review may offer a more comprehensive understanding of ATM key role in maintaining brain homeostasis integrity from the stem cell level. Moreover, it adds a more complex perspective on AT pathogenesis and opens novel avenues for future therapeutic interventions.
2025-09-23 | Nuclear rupture in confined cell migration triggers nuclear actin polymerization to limit chromatin leakage.
Upon cell migration in confined space, such as during cancer metastasis, mechanical forces from the extracellular matrix act onto the nucleus leading to nuclear envelope (NE) rupture, chromatin leakage and genomic instability. Here we found that during confined migration, NE rupture triggers dynamic nuclear F-actin formation dependent on the formins DIAPH1 and DIAPH3. We show that DIAPH3 dynamically and transiently relocates to the nucleus upon NE rupture. Interfering with DIAPH1/3 or with nuclear actin polymerization resulted in nuclear instability during confined migration. Notably, nuclear formin activity or actin assembly limit NE rupture-induced chromatin leakage. Similarly, silencing of Ataxia Telangiectasia and Rad3-related protein (ATR) reduced NE rupture-triggered nuclear F-actin assembly and increased chromatin leakage. Consistent with this, ATR promotes the phosphorylation of DIAPH3 at S1072 adjacent to its autoregulatory domain to promote nuclear actin polymerization. Using atomic force microscopy, we found that nuclear actin assembly or nuclear DIAPH3 activity promotes nuclear stiffness in an ATR-dependent manner. Thus, our study identifies an ATR-formin module that regulates nuclear mechanical properties through induction of intranuclear actin scaffolding.
2025-07-29 | DHX9 phosphorylation at S321 by ATM regulates DHX9 retention at DNA double-strand break sites and interaction with BRCA1.
To preserve genome stability, the repair of DNA double-strand breaks (DSBs) that can be caused by exposure to ionizing radiation and certain anticancer drugs is of paramount importance. Recently, it became evident that various DNA-RNA helicases play a pivotal role in homologous recombination (HR) repair and non-homologous end joining, which are the two principal DSB repair machineries in mammalian cells. In a previous study, we reported that DHX9, which belongs to the DExH-box helicase family, is involved in HR repair. However, the regulatory mechanisms governing the function of DHX9 remains elusive. The present study has demonstrated that upon etoposide treatment, DHX9 was phosphorylated at S321 in a manner dependent on ataxia telangiectasia mutated (ATM), a protein kinase. In addition, cell cycle synchronization and fractionation analysis of cell extracts revealed that only chromatin-bound DHX9 was phosphorylated by ATM in the S phase, where HR repair functions. Furthermore, by live-cell imaging with unphosphorylated-mutant and phospho-mimic DHX9, we revealed that the S321 phosphorylation of DHX9 was required for the retention of DHX9 at DSB sites but not for the initial recruitment of DHX9 to DSB sites. The DSB repair efficiencies were found to be reduced in both cell lines expressing either the unphosphorylated mutant or the phospho-mimic DHX9. Consistent with this, phospho-mimic DHX9 showed reduced interaction with BRCA1. In conclusion, our findings indicate that the DSB-induced ATM-dependent phosphorylation of DHX9 at S321, which should be dynamically regulated, is crucial for efficiency of the DSB repair.
2025-06-01 | Overexpression of thioredoxin 1 contributes to neuroprotection through ATM activation and pentose phosphate pathway modulation after traumatic brain injury.
Traumatic brain injury (TBI) induces oxidative stress, leading to secondary injury and neuronal apoptosis. The thioredoxin (Trx) system, a key regulator of redox homeostasis, and the pentose phosphate pathway (PPP), the primary source of NADPH, play critical roles in mitigating oxidative damage. This study investigates the neuroprotective effects of Trx1 in modulating oxidative stress through the Trx1-ATM-PPP axis. Adenovirus-mediated Trx1 overexpression was performed in a controlled cortical impact (CCI) mouse model four weeks prior to injury. Neuronal apoptosis, G6PD activity, NADPH levels, and ATM phosphorylation (P-ATM) were evaluated post-CCI. Behavioral deficits were assessed one week post-injury. In vitro, primary neurons were subjected to scratch injury and analyzed for Trx1 effects on P-ATM, G6PD, and NADPH. Trx1 overexpression significantly reduced neuronal apoptosis in vivo and in vitro. P-ATM levels were elevated following CCI, and Trx1 overexpression further enhanced P-ATM without altering total ATM expression. G6PD activity and NADPH levels were significantly increased in the Trx1-overexpression group, indicating upregulation of PPP flux. Behavioral assessments revealed improvements in exploratory behavior, anxiety, and memory in CCI mice with Trx1 overexpression. Trx1 mitigates secondary injury in TBI by enhancing PPP flux through ATM phosphorylation, promoting NADPH production and reducing oxidative stress. These findings identify the Trx1-ATM-PPP axis as a potential therapeutic target for TBI treatment.
gene therapies
2026-04-09 | Clinical and therapeutic impact of newborn screening-based early detection of ataxia-telangiectasia.
Not available.
2026-03-16 | Case Report: Ataxia telangiectasia with severe hemorrhagic cystitis.
Ataxia telangiectasia (AT) is a rare autosomal recessive genetic disorder caused by variants in the ataxia-telangiectasia mutated (ATM) gene. AT is characterized by progressive cerebellar degeneration, telangiectasia, immunodeficiency, cancer susceptibility, and radiosensitivity. This report presents a case of classic AT complicated by severe hemorrhagic cystitis, a rare clinical manifestation. Genetic analysis revealed novel variants in the ATM gene. A 12-year-old Han Chinese boy presented with recurrent gross hematuria that progressed in frequency and severity after completion of chemotherapy for T-cell acute lymphoblastic leukemia (ALL). He had developed gait instability at age 2, and brain MRI showed cerebellar atrophy. Genetic testing revealed compound heterozygous ATM variants: c.8357G>T (p.Gly2786Val) (maternal) and IVS54+3A>C (paternal) (NM_000051). Cystoscopy revealed multiple telangiectatic lesions of the bladder mucosa with associated yellow-brown sedimentation. Emergency cystoscopic electrocoagulation controlled the bleeding. We report two novel ATM variants (c.8357G>T, IVS54+3A>C) in a patient with classic AT who developed severe hemorrhagic cystitis associated with bladder wall telangiectasia. AT patients may be at risk for delayed, potentially life-threatening hemorrhagic cystitis, particularly following cyclophosphamide exposure. Cystoscopy is essential for diagnosis and enables timely endoscopic management.
2026-02-19 | Novel genetic variants identification and immune profiling in ataxia telangiectasia patients
Abstract Background Ataxia telangiectasia (AT) is an autosomal recessive neurodegenerative disease. While heterozygous relatives of AT patients are known to be clinically healthy, a predisposition to various pathologies has been reported. Our aim was firstly, to further characterize the clinical features and broaden the spectrum of genetic pathogenic variants in AT patients. Secondly, we aimed to study the immune profiles of AT patients and their relatives to identify similarities or common biomarkers. Methods A Target Gene Sequencing for six patients suspected with AT was performed. Computational analysis was conducted to assess the pathogenicity of novel variants. The distribution of immune cells was assessed by flow cytometry in patients with AT, AT-like disorder, Friedreich ataxia, and in AT relatives. The expression pattern of candidate genes was evaluated by RT-qPCR. Results We identified and predicted the pathogenicity of novel variants in the ATM gene. Computational analysis suggested that the novel identified missense mutation could affect ATP binding pattern and ATM protein flexibility, while Alu element insertion could probably induces a premature stop codon. Furthermore, our results confirm the pathogenic effect of identified splicing mutations on the ATM transcript. Moreover, we noticed a high percentage of LTCD4 + and LTCD8 + senescent subsets in AT patients and a relative increase of the of intermediate and non-classical monocytes accompanied with a decrease of classical monocytes specifically in AT patients with truncated biallelic mutations which was intriguingly similar to the immune profile of AT parents. In addition, a difference of immune pattern was observed between AT patients with biallelic truncated mutations compared to those with at least one non-truncated mutation, with a variability intragroup. Gene expression analysis identified FOXO3, IL33 and METTL3 as putative genes that may yield clues into AT pathogenesis. Conclusion Taken together, our study expands the mutational spectrum of AT disease worldwide and further characterize the immune profile of AT patients uncovering a possible difference in some immune cellular subsets related to ATM mutation type and delineate putative immune abnormalities related to ATM heterozygosity among AT parents. Furthermore, dysregulation in FOXO3, IL33 and METTL3 expression could be related to disease severity.
2026-01-23 | Phenotypic characterization and cancer risk related to homozygous and heterozygous mutations in the ataxia-telangiectasia mutated gene
The ataxia-telangiectasia mutated (ATM) gene plays a critical role in DNA damage repair and functions as a tumor suppressor. Homozygous mutations in the ATM gene cause ataxia-telangiectasia (A-T), a rare autosomal recessive disorder characterized by progressive neurodegeneration, immunodeficiency, radiosensitivity, and a markedly increased risk of malignancy. In contrast, individuals carrying heterozygous ATM mutations are phenotypically normal but demonstrate an elevated susceptibility to cancer, particularly breast cancer. This review aimed to summarize current knowledge on the phenotypic manifestations associated with both homozygous and heterozygous ATM mutations and evaluate their relationship to cancer risk. A total of 98 published studies were reviewed, alongside data from established genetic databases including OMIM, GeneCards, UniProt, and GeneReviews. Evidence indicated that A-T patients with homozygous ATM mutations are at high risk for malignancies, with lymphoid cancers such as leukemia and lymphoma predominating in individuals under 20 years of age, while solid tumors are more frequently observed in adults. Heterozygous ATM mutation carriers exhibited a significantly increased risk of cancer, most notably breast cancer, with emerging data suggesting elevated risk in males as well. Further large-scale and longitudinal studies are required to more precisely quantify cancer risk associated with ATM mutations and to improve surveillance, genetic counselling, and clinical management strategies.
2025-12-30 | Variant ataxia-telangiectasia presenting as tremor-dystonia syndrome in a bulgarian religious minority
Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder due to mutations in the ATM-gene. Given the residual kinase activity and the type of ATM mutation, its clinical spectrum is varying from a severe classic phenotype to a variant atypical form.The study included 28 patients, belonging to four big Bulgarian Muslim pedigrees with tremor and dystonia. Whole exome sequencing was performed in 7 affected from 2 unrelated pedigrees, followed by Sanger sequencing of the coding sequences and exon/intron borders of the ATM gene.Twenty four of the affected were homozygous for c.8147T>C (p.Val2716Ala) in ATM, while four of the affected were compound heterozygous. The targeted Sanger sequencing along the ATM gene revealed as a second mutation in three of them the splice-site variant c.4909+1G>A and in one patient a synonymous pathogenic variant with splicing effect c.3576G>A, p.Lys1192. The age at onset in our group varies between 14 days and 40 years. The main symptoms are dystona and tremor, more prominent in the upper limbs and the neck, dystonic dysarthria and dysphagia. The clinical course was very slowly progressive. Brain imaging was normal in the majority of them.Clinical features, due to mutations in ATM gene can be very broad. The disease may appear as dystonia, especially of early onset, without frank cerebellar involvement and also normal cerebral imaging. A-T should be considered in all patients with unexplained, even mild movement disorders and elevated alpha fetoprotein.
oligonucleotides
2026-03-12 | Interferon stimulatory DNA activates the DNA damage signaling through ATM and DNA-PK sensing.
In eukaryotic cells, DNA is normally confined in the nucleus and mitochondria and the presence of DNA in the cytoplasm is a danger signal that activates innate immune responses. Upon detection of cytoplasmic dsDNA in mammalian cells, the cGAS-STING pathway induces type I-Interferon and inflammatory responses, a key step in innate immune activation. Since its discovery, Interferon Stimulatory DNA (ISD), a linear double-stranded DNA, has been largely used to study the cGAS-STING pathway and its regulation. Here, we show that ISD also stimulates DNA damage signaling. We show that ISD activates both ataxia telangiectasia mutated and DNA-dependent protein kinase, the sensor kinases of the DNA damage response, independently of cGAS-STING signaling. Our results demonstrate that the DNA damage response, which is usually considered a response to genomic DNA lesions, can be promoted by foreign DNA. Our data further suggest that ISDs coordinate two central protective functions of cells, the innate immunity and DNA damage checkpoints.
2025-10-29 | Lets talk about ataxia-telangiectasia: Meeting report of the AT clinical research conference June 2025.
Almost fifty years after the identification of ataxia telangiectasia (A-T) as a radiosensitive disorder and thirty years following the identification of ataxia telangiectasia mutated (ATM) as the defective gene, clinicians and scientists gathered at Loughborough University, UK from June 25th -27th 2025 for an Ataxia Telangiectasia Clinical Research Conference. The mix of expertise of clinicians and scientists with basic and translational expertise ensured that a focus was on how to exploit our knowledge of ATM's function to clinical benefit. Considerable emphasis was placed on the role of ATM in the DNA damage response and the consequences in this multisystem disease, including the neurodegenerative phenotype. The increasingly recognized role of ATM in oxidative stress was also considered and how it was pertinent to mitochondrial dysfunction, metabolic abnormalities and energy metabolism in A-T. The implications of these roles of ATM in protecting the genome/cell and the development of new technology, such as organoids, were widely discussed in the clinical setting of patients with A-T. An important contribution to the meeting was the description of pathways /mechanisms that have led to the development of therapeutic approaches for A-T including the use of specific antisense oligonucleotides to restore ATM function in patients; delivery of full-length ATM cDNA to A-T cells; eDSP (formerly EryDex) that encapsulates dexamethasone sodium phosphate in a patient's own red blood cells and the use of small molecules (triheptanoin, nicotinamide riboside and N-acetyl leucine) to correct mitochondrial and metabolic function.
2025-08-09 | Impact of specific productivity and operation mode upon the biophysical properties of HIV-1 Gag-based virus-like particles.
Virus-like particles (VLPs) are non-infective vaccine candidates that have gained interest given their natural ability to elicit strong immune responses. Particularly, HIV-1 Gag-based VLPs are one of the most described platforms for vaccine development, provided their ability for successful pseudotyping either by genetic engineering or click chemistry. When Gag polyprotein is recombinantly expressed, VLPs are naturally assembled in the vicinity of the cell membrane and then secreted by cell budding, taking part of the host cell membrane. Their properties are dependent upon the cell line and manufacturing method. Although great advancements toward the implementation of analytical methods have been made, VLP quality attributes are quite unclear whenever production is enhanced by metabolic engineering or process intensification strategies. This work offers a comparative study of VLP quality attributes upon transient gene expression (TGE) in HEK293 cell cultures operated in batch and perfusion mode. Moreover, the impact of specific productivity is also studied by ataxia telangiectasia mutated (ATM) gene silencing, which has been reported to enhance fourfold VLP production. A linear negative correlation was found between the ratio of Gag monomers/VLP and specific productivity. 3100 ± 100 monomers/VLP were obtained for the standard batch production, dropping to 1900 ± 100 and 800 ± 60 for the perfusion and batch ATM-knockdown conditions, respectively. Furthermore, functionalization rates were measured in terms of Cy5 per total particles (TP). Both perfusion-derived nanoparticles achieved functionalization rates of 2800 Cy5/TP. On the contrary, those nanoparticles produced in batch yielded functionalization rates below 1000 Cy5/TP. Moreover, a complete lipidome analysis revealed a relative decrease in the quantity of lipid/particle for all studied conditions in comparison to the standard batch production. Finally, all VLP samples were characterized to assess the impact of the differential physicochemical properties upon purification and stability rates. KEY POINTS: • VLP quality inversely correlates with Gag-specific productivity and operation mode. • Functionalization and lipid content drop with metabolic burden or ATM silencing. • Perfusion enables high VLP recovery and lyophilization with preserved morphology.
2025-01-03 | Targeted knockdown of ATM, ATR, and PDEδ increases Gag HIV-1 VLP production in HEK293 cells.
Several strategies have been developed in recent years to improve virus-like particle (VLP)-based vaccine production processes. Among these, the metabolic engineering of cell lines has been one of the most promising approaches. Based on previous work and a proteomic analysis of HEK293 cells producing Human Immunodeficiency Virus-1 (HIV-1) Gag VLPs under transient transfection, four proteins susceptible of enhancing VLP production were identified: ataxia telangiectasia mutated (ATM), ataxia telangiectasia and rad3-related (ATR), DNA-dependent protein kinase catalytic subunit (DNA-PKcs), and retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta (PDEδ). The knockdown of ATM, ATR, and PDEδ in HEK293 cells increased HIV-1 VLP titers in the supernatant by 3.4-, 2.1-, and 2.2-fold, respectively. Also, possible metabolic synergies between plasmids were investigated by statistical design of experiments (DoE), enabling us to identify the optimal production strategy, that was further demonstrated at lab-scale stirred tank bioreactor operated in perfusion, significantly increasing both VLPs specific and volumetric productivities to 8.3 × 103 VLPs/cellxday and 7.5 × 1012 VLPs/Lxday, respectively. KEY POINTS: • ATM, ATR, and PDEδ knockdowns increased VLP production in HEK293 cells. • Knockdown of ATM increased budding efficiency and extracellular vesicle concentration. • ATM knockdown could be intensified to bioreactor scale operated in perfusion.
2024-08-07 | The importance of synthetic pharmacotherapy for recessive cerebellar ataxias.
The last decade has witnessed major breakthroughs in identifying novel genetic causes of hereditary ataxias, deepening our understanding of disease mechanisms, and developing therapies for these debilitating disorders. This article reviews the currently approved and most promising candidate pharmacotherapies in relation to the known disease mechanisms of the most prevalent autosomal recessive ataxias. Omaveloxolone is an Nrf2 activator that increases antioxidant defense and was recently approved for treatment of Friedreich ataxia. Its therapeutic effect is modest, and further research is needed to find synergistic treatments that would halt or reverse disease progression. Promising approaches include upregulation of frataxin expression by epigenetic mechanisms, direct protein replacement, and gene replacement therapy. For ataxia-telangiectasia, promising approaches include splice-switching antisense oligonucleotides and small molecules targeting oxidative stress, inflammation, and mitochondrial function. Rare recessive ataxias for which disease-modifying therapies exist are also reviewed, emphasizing recently approved therapies. Evidence supporting the use of riluzole and acetyl-leucine in recessive ataxias is discussed. Advances in genetic therapies for other neurogenetic conditions have paved the way to implement feasible approaches with potential dramatic benefits. Particularly, as we develop effective treatments for these conditions, we may need to combine therapies, consider newborn testing for pre-symptomatic treatment, and optimize non-pharmacological approaches.
other
2026-04-13 | Cell-Based Therapies for Spinocerebellar Degenerations: A Systematic Review of Human Clinical Evidence.
Spinocerebellar degenerations (SCDs) are progressive hereditary and selected sporadic cerebellar neurodegenerative disorders with limited disease-modifying options. Cell-based therapies particularly, mesenchymal stromal/stem cells (MSCs), neural stem/progenitor cells, olfactory ensheathing cells (OECs), cord blood mononuclear cells (CBMCs), and hematopoietic stem cell transplantation (HSCT) are biologically plausible candidates, but their clinical efficacy and safety remain uncertain. We searched MEDLINE/PubMed, Embase, Scopus, Web of Science, and Cochrane Library from inception to 10 October 2025 (no language restrictions). The OSF-registered protocol prespecified eligibility, outcomes, and design-specific risk-of-bias (RoB) tools, with harmonized overall RoB judgments. We included human interventional or observational reports of cell-based or cell-derived products in hereditary ataxias and selected cerebellar-predominant degenerative syndromes within the OPCA/MSA-C spectrum, and extracted clinical efficacy, safety, and follow-up. Of 603 records screened, 17 reports met the protocol-defined inclusion criteria (15 full texts; 2 abstracts; 2006–2025). Most were small, uncontrolled case series, predominantly from China. Cell types: MSCs (9/17), HSCT in ataxia-telangiectasia (3/17), OECs (3/17), and others (neural stem cells [NSCs], CBMCs; 2/17). Routes were intrathecal and/or intravenous for MSC/CBMC; OEC/NSC were intracerebral/intraspinal; HSCT was delivered intravenously. Primary follow-up was typically 1–6 months. Safety was generally acceptable for MSC/CBMC/OEC with no treatment-related deaths and mostly transient post-procedural symptoms; HSCT exhibited regimen-related toxicities consistent with conditioning intensity. Efficacy signals were modest and often transient: short-term International Cooperative Ataxia Rating Scale (ICARS) improvements were reported across multiple series. Cell-based therapies for SCDs show biological plausibility and generally reassuring short-term safety, but current human evidence, dominated by uncontrolled, high-bias studies does not establish efficacy or durability. Priority should shift to rigorously controlled trials, standardized good manufacturing practice (GMP)-characterized products, blinded centralized ratings, careful control of co-interventions, and objective biomarkers.
2025-07-19 | Neurological Complications in Inborn Errors of Immunity: A Scoping Review of Clinical Spectrum, Pathophysiological Mechanisms, and Therapeutic Strategies.
Inborn errors of immunity (IEIs) are traditionally viewed as monogenic disorders of the immune system, but mounting evidence indicates that they often have underappreciated impacts on the nervous system. We review the emerging intersection between IEIs and neurological diseases, spanning neurodevelopmental and neurodegenerative manifestations. We discuss how genetic overlaps between immunity and brain development-for example, defects in DNA repair, chromatin remodeling, or cytokine signaling-can lead to combined immunological and neurological phenotypes. Clinical data from patient cohorts highlight that a substantial subset of IEIs present with neurodevelopmental disorders (such as autism spectrum disorder, intellectual disability, or ADHD) and/or neurodegenerative diseases (such as progressive ataxia, motor regression, or cognitive decline). These comorbidities arise through diverse mechanisms, including direct roles of immune genes in neural development, the impact of chronic inflammation on the brain, and metabolic byproducts toxic to neural tissue. We illustrate these mechanisms with examples such as ataxia-telangiectasia (a DNA repair defect causing immunodeficiency and cerebellar degeneration) and DiGeorge syndrome (a developmental immunodeficiency often initially diagnosed as autism). The translational importance of these insights is profound-recognizing neurological involvement in IEIs can improve early diagnosis and multidisciplinary care, whereas a deeper understanding of immune-neural crosstalk opens avenues for novel therapies (such as targeted anti-inflammatory treatments or gene therapies that address both immune and neural dysfunction). By integrating immunology and neuroscience perspectives, this comprehensive review sheds light on the immune underpinnings of certain neurologic diseases and underscores the importance of collaborative management for patients at this complex interface.
2025-06-26 | Sarcoidosis-like Skin Lesions as the First Manifestation of Ataxia-Telangiectasia.
Ataxia-telangiectasia is a rare autosomal recessive disorder that is difficult to diagnose due to its unpredictable presentation. It is characterized by cerebellar degeneration, telangiectasias, immunodeficiency, frequent pulmonary infections, and tumors. Immune system abnormalities manifest as disruptions in both cellular and humoral immunity. The most common findings include decreased levels of immunoglobulin classes (IgA, IgM, IgG, and IgG subclasses) and a reduced number of T and B lymphocytes. A four-year-old girl was initially evaluated and treated for skin lesions that presented as crusts spreading across her body. She was monitored by a pulmonologist due to frequent bronchial obstructions. Over time, she developed bilateral scleral telangiectasia, saccadic eye movements, and impaired convergence. Her gait was wide-based and unstable, with truncal ataxia and a positive Romberg sign. Laboratory tests revealed decreased immunoglobulin G levels, subclass IgG4 levels, elevated alpha-fetoprotein, and a reduced number of T and B lymphocytes. Brain magnetic resonance imaging showed cerebellar atrophy. Whole-exome sequencing identified heterozygous variants c.1564-165del, p.(Glu5221lefsTer43), and c.7630-2A>C in the serine/threonine-protein kinase ATM (ataxia-telangiectasia mutated) gene, confirming the diagnosis of ataxia-telangiectasia. Following diagnosis, treatment with intravenous immunoglobulin replacement was initiated along with infection prevention and management. The goal of this case report is to raise awareness of the atypical initial presentation that may lead to a diagnostic delay. We emphasize the importance of considering ataxia-telangiectasia in the differential diagnosis, even when classical neurological signs are not yet evident.
2023-10-31 | Ataxia Telangiectasia in Latin America: clinical features, immunodeficiency and mortality in a multicenter study
Abstract Ataxia-telangiectasia (AT) is a rare neurodegenerative genetic disorder leading to neurological defects, telangiectasias and immunodeficiency. We aimed to study the clinical and immunological features of Latin American patients with AT and analyze the factors associated with AT-related mortality. Referral centers ( n = 46) from 9 Latin American countries participated in this retrospective cohort study. AT was defined with ESID Criteria. Designated physicians in each healthcare center reviewed medical records of 218 patients with AT. Data from 218 patients with AT were analyzed. Mean ± standard deviation ages at symptom onset and diagnosis were 1.6 ± 1.1 and 5.7 ± 3.5 years, respectively. Most (66.9%) patients presented recurrent airway infections, which was significantly associated with IgA deficiency. Humoral deficiencies included IgA deficiency in 60.8% of patients and IgG deficiency in 28.6%. Lymphopenia was present in most cases, mainly affecting T and B cells. Around half of patients used antibiotic prophylaxis (57.7%) and immunoglobulin replacement (49.1%). No complications due to live viral vaccines were reported. Their mean survival was 24.2 years and Kaplan-Meier 20-year-survival rate was 52.6%. Low IgG levels were associated with decreased life expectancy (hazard ratio 2.1; 95% CI, 1.11–3.93), whereas male sex was a protecting factor (hazard ratio 0.52; 95% CI, 0.27–0.99). There was a high frequency of recurrent infections and immunologic abnormalities in our sample of patients with AT. Higher mortality was associated with female gender and low IgG levels. These findings suggest that immunologic status should be investigated in all patients with AT, thus helping us to improve therapeutic strategies.
2023-01-24 | Successful Treatment of Large B-Cell Lymphoma in a Child with Compound Heterozygous Mutation in the ATM Gene.
Ataxia-telangiectasia (AT) is a multisystemic neurodegenerative inborn error of immunity (IEI) characterized by DNA repair defect, chromosomal instability, and hypersensitivity to ionizing radiation. Impaired DNA double-strand break repair determines a high risk of developing hematological malignancies, especially lymphoproliferative diseases. Poor response to treatment, excessive chemotherapy toxicities, and the need for avoiding exposure to ionizing radiation make the successful clinical management of patients with AT challenging for oncologists. We describe the favorable outcome of the LBCL with IRF4 rearrangement at stage III in a 7-year-old female patient diagnosed with AT. The patient was treated according to the B-HR arm of the INTER-B-NHL-COP 2010 protocol, including the administration of rituximab, cyclophosphamide, methotrexate, prednisone, etc. She presented excessive treatment toxicities despite individually reduced doses of methotrexate and cyclophosphamide. However, in the MRI there was no significant reduction in pathologic lymph nodes after three immunochemotherapy courses. Therefore, a lymph node biopsy was taken. Its subsequent histopathological examination revealed tuberculosis-like changes, though tuberculosis suspicion was excluded. After two following immunochemotherapy courses, PET-CT confirmed complete remission. From March 2022 onwards, the patient has remained in remission under the care of the outpatient children's oncology clinic.
small molecules
2026-08-17 | Emerging roles of ATR beyond DNA damage repair: orchestrating transcriptional reprogramming during epithelial-to-mesenchymal transition.
The ability of cancer cells to transition between epithelial and mesenchymal states, a process known as epithelial-to-mesenchymal transition (EMT), is a key driver of cancer metastasis and therapy resistance. While ataxia telangiectasia and Rad3-related (ATR) kinase was originally characterized as a responder to DNA damage and replication stress, recent discoveries implicate a critical role for ATR in EMT and metastasis. Two pivotal studies published in this issue of JCI provide key insights into how ATR intersects with EMT transcriptional reprogramming. Patel et al. demonstrated that ATR prevented R-loop accumulation at EMT-related gene loci, thereby facilitating the transcriptional reprogramming necessary for EMT as well as tumor growth and metastasis. Tu et al. further uncovered a role for ATR in ECM stiffness-induced EMT, which was associated with an immunosuppressive tumor microenvironment. Together, these studies highlight important therapeutic implications for ATR targeting in the context of metastasis and therapy resistance.
2026-07-31 | Exploiting the weak link: Ataxia-Telangiectasia Mutated dysfunction in oesophagogastric tumours.
ATM (ataxia-telangiectasia mutated) is a central regulator of the DNA damage response, coordinating double-strand break repair, checkpoint control, and cell fate decisions. Its disruption drives genomic instability and has been implicated across multiple tumour types. In oesophagogastric cancers, ATM alterations occur in a clinically relevant subset of cases, encompassing both somatic and germline events, and are associated with distinct molecular features including reduced co-occurrence with TP53 mutations and elevated homologous recombination deficiency scores. This narrative review synthesises published literature and publicly available genomic databases to examine ATM biology, the spectrum of ATM alterations across oesophageal adenocarcinoma, oesophageal squamous cell carcinoma, and gastric cancer subtypes, and the challenges of defining true ATM deficiency. The therapeutic implications of ATM dysfunction are evaluated across radiotherapy, platinum-based chemotherapy, ATR inhibition, and PARP inhibition. ATM alterations are detected in approximately 6% of tumours pan-cancer and in up to 10% of oesophagogastric cases. Defining ATM deficiency remains challenging, as immunohistochemistry, next-generation sequencing, and functional assays each carry distinct limitations. ATR inhibition emerges as the most consistently supported therapeutic strategy, with converging preclinical and early clinical evidence across oesophagogastric models. By contrast, available data do not support treating ATM deficiency as equivalent to BRCA-like homologous recombination deficiency, and PARP inhibitor monotherapy has not demonstrated consistent benefit. Prospective validation of functional ATM assays, histology-stratified trial design, and integration of genomic, protein-level, and functional evidence represent key priorities for translating ATM-guided strategies into oesophagogastric cancer practice.
2026-07-28 | Spatiotemporal regulation of DNA repair proteins between Golgi and nucleus maintains genome stability.
The Golgi complex serves as a critical hub for cellular homeostasis, yet its communication with the nucleus remains largely unexplored. By analyzing and siRNA-validating localization data from the Human Protein Atlas, we uncovered substantial proteome interconnectivity between the Golgi and nucleus, including an unexpected enrichment for DNA repair factors. We identify a cluster of DNA damage response (DDR) proteins occupying distinct sub-Golgi compartments that redistribute dynamically between the Golgi and nucleus in response to genotoxic stress, with the type of DNA lesion shaping the direction of redistribution. Focusing on the homologous recombination (HR) regulator RAD51C, we show that DNA damage triggers ataxia telangiectasia mutated (ATM)-dependent release of a giantin-tethered Golgi RAD51C pool, with subsequent importin-β-dependent nuclear import, where repair-associated foci form. Giantin depletion prematurely releases RAD51C, producing aberrant nuclear foci lacking key DDR markers, reducing ATM activation and HR efficiency, elevating genome instability, and accelerating proliferation. The Golgi thus acts as a spatiotemporal coordination node for DDR factors safeguarding genomic stability.
2026-07-22 | MPT0E028, a pan-HDAC inhibitor, ameliorates bleomycin-induced pulmonary fibrosis by promoting AT2-to-AT1 differentiation through the ATM/AMPK/FoxO1 pathway.
Persistent injury and impaired regeneration of the alveolar epithelium are key contributors to the pathogenesis of pulmonary fibrosis. In idiopathic pulmonary fibrosis (IPF), type 2 alveolar epithelial (AT2) cells fail to fully differentiate into type 1 alveolar epithelial (AT1) cells, remaining instead in a transitional state. Histone deacetylase (HDAC) inhibitors are promising therapeutic agents for pulmonary fibrosis. Therefore, this study investigated whether MPT0E028, a pan-HDAC inhibitor, ameliorated bleomycin (BLM)-induced pulmonary fibrosis in a therapeutic model of mice by promoting AT2-to-AT1 cell differentiation. The effects of MPT0E028 on pulmonary fibrosis were assessed by evaluating the expression of fibrogenic proteins and cell markers of AT1 (T1α and aquaporin 5 [AQP5]), AT2 (surfactant protein C [SPC]) and alveolar epithelial transitional cells (Keratin 8 [KRT8]) in a therapeutic model of BLM-induced pulmonary fibrosis in mice. The role of the ataxia-telangiectasia mutated (ATM)/AMP-activated protein kinase (AMPK)/forkhead box O1 (FoxO1) signaling pathway in MPT0E028-induced T1α expression was examined in murine AT2 cells (MLE-12 cells). Administration of MPT0E028 significantly reduced fibrosis scores; suppressed the expression of connective tissue growth factor, collagen I, fibronectin, and α-smooth muscle actin; and improved lung function in the therapeutic model of BLM-induced pulmonary fibrosis in mice. MPT0E028 enhanced the expression of T1α and AQP5 but reduced the expression of SPC and KRT8 in lung tissues from BLM-treated mice. In MLE-12 cells and primary human AT2 cells, MPT0E028 upregulated T1α and AQP5 expression in a time-dependent manner, with this accompanied by a decrease in SPC expression. AS1842856, an FoxO1 inhibitor, and FoxO1 siRNA transfection inhibited MPT0E028-stimulated T1α expression, whereas transfection with FoxO3 siRNA had no effect. FoxO1 siRNA transfection also inhibited MPT0E028-stimulated T1α-luciferase activity. MPT0E028 induced FoxO1 serine phosphorylation, increased FoxO1 recruitment to the T1α promoter, and enhanced FoxO1-luciferase activity. Compound C, an AMPK inhibitor, and AMPK siRNA transfection suppressed MPT0E028-stimulated T1α expression, and compound C also inhibited MPT0E028-promoted FoxO1 recruitment to the T1α promoter. MPT0E028 induced AMPK phosphorylation in a time-dependent manner and increased ATM acetylation and phosphorylation in MLE-12 cells. ATM siRNA transfection suppressed MPT0E028-induced T1α expression, AMPK and FoxO1 serine phosphorylation, FoxO1 recruitment to the T1α promoter, and FoxO1-luciferase activity. MPT0E028 induced FoxO1 phosphorylation in AT2 cells in the therapeutic model of BLM-induced pulmonary fibrosis in mice. MPT0E028 is the first pan-HDAC inhibitor shown to activate ATM acetylation-mediated AMPK/FoxO1 signaling to induce AT2-to-AT1 differentiation in a therapeutic model of BLM-induced pulmonary fibrosis in mice. Administration of MPT0E028 after BLM challenge effectively ameliorated pulmonary fibrosis by suppressing fibrogenic protein expression and promoting AT2-to-AT1 cell differentiation. These results suggest that MPT0E028 holds potential as a therapeutic agent for IPF treatment.
2026-07-17 | Identification of dual-targeting PROTACs for ataxia telangiectasia and RAD3-related and aurora kinase A as chemo-sensitizers for leukemia cells.
The ataxia telangiectasia and RAD3-related (ATR) kinase is a central regulator of DNA damage responses. Its pharmacological degradation by proteolysis-targeting chimeras (PROTACs) represents a promising strategy to sensitize cancer cells to DNA-damaging chemotherapy. It is currently unknown if ATR PROTACs can be pharmacologically designed to target a second cancer-relevant kinase. In this study, we report the design, synthesis, and biological evaluation of novel cereblon (CRBN)-based PROTACs for ATR. Structure-guided design and chemical synthesis enabled the development of a focused library of degraders based on selective ATR inhibitors and optimized CRBN ligands. Among the synthesized compounds, Abd141 turns out as the most promising degrader, showing potent ATR degradation in human leukemia cells, without affecting ATM, WEE1 or DNA-PKcs. Consistently, the developed PROTACs prove activity in an in vitro ATR/ATRIP binding assay. Abd141 exhibits high chemical, microsomal, and plasma stability, and no cytotoxicity in non-cancerous HEK293 cells. Proteomic studies and immunoblot experiments identify aurora kinase A (AURKA) as additional target of CRBN-induced proteasomal degradation by Abd141. Dose-degradation studies of Abd141 in the MOLT-4 cell line yielded a DC50 of 97.7 nM for ATR and 6.7 nM for AURKA. These findings disclose Abd141 as effective dual ATR/AURKA degrader and innovative chemo-sensitizer that encourages preclinical development.
proteins
2026-06-22 | A point mutation in the FAT domain constitutively increases the kinase activity of Rad3ATR and bypasses the requirement for 9-1-1 phosphorylation to activate the DNA replication checkpoint.
Ataxia telangiectasia and Rad3-related (ATR) initiates cell cycle checkpoints to maintain genome integrity in the presence of replication stress or various forms of DNA damage. However, how ATR is activated for checkpoint initiation remains incompletely understood. The canonical model suggests that binding of an ATR-activator protein relieves the autoinhibitory PIKK regulatory domain (PRD) within the kinase domain, thereby activating ATR by granting substrate access to the catalytic centre. To better understand the checkpoint initiation mechanism, we conducted a genetic screen in fission yeast that identified a charge-reversal mutation, E1369K, in the conserved FRAP-ATM-TRRAP (FAT) domain of Rad3, the ortholog of ATR. In vitro kinase assays show that the mutation converts Rad3 into a constitutively active form. This allows rescue of the Rad3 kinase signaling defect in cells lacking the phosphorylation of the Rad9-Rad1-Hus1 (9-1-1) complex specifically in the DNA replication checkpoint, not the damage checkpoint pathway. Since the mutation is not in the kinase domain and is away from the PRD, these findings show that, in addition to the canonical mechanism, Rad3 may also be activated allosterically via the FAT domain, a mechanism likely conserved in higher eukaryotes.
2026-05-01 | The multifaceted role of ATM protein in neural stem/progenitor cell biology and neurogenesis: beyond DNA damage response.
The Ataxia Telangiectasia Mutated (ATM) protein kinase is a well recognized master regulator of the DNA damage response (DDR) and cell cycle control whose dysfunction leads to the rare neurological disorder Ataxia Telangiectasia (AT). A mounting body of evidence has revealed unequivocally that ATM relevance extends far beyond its DDR role and includes critical non-canonical functions. This minireview summarizes the current knowledge on ATM role in neural stem progenitor cell (NSPC) biology and in neurogenesis. In particular, herein we highlight how ATM is crucial for NSPC proliferation, differentiation, and survival, acting not only as a guardian of genomic integrity but also as a key orchestrator of developmental timing. Furthermore, we discuss how ATM deficiency in AT leads to dysregulated NSPC proliferation, premature neuronal maturation, and impaired quality control during neurogenesis, potentially contributing to progressive neurodegeneration and complex neurological symptoms associated with this pediatric disorder. By integrating canonical and non-canonical mechanisms, this review may offer a more comprehensive understanding of ATM key role in maintaining brain homeostasis integrity from the stem cell level. Moreover, it adds a more complex perspective on AT pathogenesis and opens novel avenues for future therapeutic interventions.
2025-09-23 | Nuclear rupture in confined cell migration triggers nuclear actin polymerization to limit chromatin leakage.
Upon cell migration in confined space, such as during cancer metastasis, mechanical forces from the extracellular matrix act onto the nucleus leading to nuclear envelope (NE) rupture, chromatin leakage and genomic instability. Here we found that during confined migration, NE rupture triggers dynamic nuclear F-actin formation dependent on the formins DIAPH1 and DIAPH3. We show that DIAPH3 dynamically and transiently relocates to the nucleus upon NE rupture. Interfering with DIAPH1/3 or with nuclear actin polymerization resulted in nuclear instability during confined migration. Notably, nuclear formin activity or actin assembly limit NE rupture-induced chromatin leakage. Similarly, silencing of Ataxia Telangiectasia and Rad3-related protein (ATR) reduced NE rupture-triggered nuclear F-actin assembly and increased chromatin leakage. Consistent with this, ATR promotes the phosphorylation of DIAPH3 at S1072 adjacent to its autoregulatory domain to promote nuclear actin polymerization. Using atomic force microscopy, we found that nuclear actin assembly or nuclear DIAPH3 activity promotes nuclear stiffness in an ATR-dependent manner. Thus, our study identifies an ATR-formin module that regulates nuclear mechanical properties through induction of intranuclear actin scaffolding.
2025-07-29 | DHX9 phosphorylation at S321 by ATM regulates DHX9 retention at DNA double-strand break sites and interaction with BRCA1.
To preserve genome stability, the repair of DNA double-strand breaks (DSBs) that can be caused by exposure to ionizing radiation and certain anticancer drugs is of paramount importance. Recently, it became evident that various DNA-RNA helicases play a pivotal role in homologous recombination (HR) repair and non-homologous end joining, which are the two principal DSB repair machineries in mammalian cells. In a previous study, we reported that DHX9, which belongs to the DExH-box helicase family, is involved in HR repair. However, the regulatory mechanisms governing the function of DHX9 remains elusive. The present study has demonstrated that upon etoposide treatment, DHX9 was phosphorylated at S321 in a manner dependent on ataxia telangiectasia mutated (ATM), a protein kinase. In addition, cell cycle synchronization and fractionation analysis of cell extracts revealed that only chromatin-bound DHX9 was phosphorylated by ATM in the S phase, where HR repair functions. Furthermore, by live-cell imaging with unphosphorylated-mutant and phospho-mimic DHX9, we revealed that the S321 phosphorylation of DHX9 was required for the retention of DHX9 at DSB sites but not for the initial recruitment of DHX9 to DSB sites. The DSB repair efficiencies were found to be reduced in both cell lines expressing either the unphosphorylated mutant or the phospho-mimic DHX9. Consistent with this, phospho-mimic DHX9 showed reduced interaction with BRCA1. In conclusion, our findings indicate that the DSB-induced ATM-dependent phosphorylation of DHX9 at S321, which should be dynamically regulated, is crucial for efficiency of the DSB repair.
2025-06-01 | Overexpression of thioredoxin 1 contributes to neuroprotection through ATM activation and pentose phosphate pathway modulation after traumatic brain injury.
Traumatic brain injury (TBI) induces oxidative stress, leading to secondary injury and neuronal apoptosis. The thioredoxin (Trx) system, a key regulator of redox homeostasis, and the pentose phosphate pathway (PPP), the primary source of NADPH, play critical roles in mitigating oxidative damage. This study investigates the neuroprotective effects of Trx1 in modulating oxidative stress through the Trx1-ATM-PPP axis. Adenovirus-mediated Trx1 overexpression was performed in a controlled cortical impact (CCI) mouse model four weeks prior to injury. Neuronal apoptosis, G6PD activity, NADPH levels, and ATM phosphorylation (P-ATM) were evaluated post-CCI. Behavioral deficits were assessed one week post-injury. In vitro, primary neurons were subjected to scratch injury and analyzed for Trx1 effects on P-ATM, G6PD, and NADPH. Trx1 overexpression significantly reduced neuronal apoptosis in vivo and in vitro. P-ATM levels were elevated following CCI, and Trx1 overexpression further enhanced P-ATM without altering total ATM expression. G6PD activity and NADPH levels were significantly increased in the Trx1-overexpression group, indicating upregulation of PPP flux. Behavioral assessments revealed improvements in exploratory behavior, anxiety, and memory in CCI mice with Trx1 overexpression. Trx1 mitigates secondary injury in TBI by enhancing PPP flux through ATM phosphorylation, promoting NADPH production and reducing oxidative stress. These findings identify the Trx1-ATM-PPP axis as a potential therapeutic target for TBI treatment.
gene therapies
2026-04-09 | Clinical and therapeutic impact of newborn screening-based early detection of ataxia-telangiectasia.
Not available.
2026-03-16 | Case Report: Ataxia telangiectasia with severe hemorrhagic cystitis.
Ataxia telangiectasia (AT) is a rare autosomal recessive genetic disorder caused by variants in the ataxia-telangiectasia mutated (ATM) gene. AT is characterized by progressive cerebellar degeneration, telangiectasia, immunodeficiency, cancer susceptibility, and radiosensitivity. This report presents a case of classic AT complicated by severe hemorrhagic cystitis, a rare clinical manifestation. Genetic analysis revealed novel variants in the ATM gene. A 12-year-old Han Chinese boy presented with recurrent gross hematuria that progressed in frequency and severity after completion of chemotherapy for T-cell acute lymphoblastic leukemia (ALL). He had developed gait instability at age 2, and brain MRI showed cerebellar atrophy. Genetic testing revealed compound heterozygous ATM variants: c.8357G>T (p.Gly2786Val) (maternal) and IVS54+3A>C (paternal) (NM_000051). Cystoscopy revealed multiple telangiectatic lesions of the bladder mucosa with associated yellow-brown sedimentation. Emergency cystoscopic electrocoagulation controlled the bleeding. We report two novel ATM variants (c.8357G>T, IVS54+3A>C) in a patient with classic AT who developed severe hemorrhagic cystitis associated with bladder wall telangiectasia. AT patients may be at risk for delayed, potentially life-threatening hemorrhagic cystitis, particularly following cyclophosphamide exposure. Cystoscopy is essential for diagnosis and enables timely endoscopic management.
2026-02-19 | Novel genetic variants identification and immune profiling in ataxia telangiectasia patients
Abstract Background Ataxia telangiectasia (AT) is an autosomal recessive neurodegenerative disease. While heterozygous relatives of AT patients are known to be clinically healthy, a predisposition to various pathologies has been reported. Our aim was firstly, to further characterize the clinical features and broaden the spectrum of genetic pathogenic variants in AT patients. Secondly, we aimed to study the immune profiles of AT patients and their relatives to identify similarities or common biomarkers. Methods A Target Gene Sequencing for six patients suspected with AT was performed. Computational analysis was conducted to assess the pathogenicity of novel variants. The distribution of immune cells was assessed by flow cytometry in patients with AT, AT-like disorder, Friedreich ataxia, and in AT relatives. The expression pattern of candidate genes was evaluated by RT-qPCR. Results We identified and predicted the pathogenicity of novel variants in the ATM gene. Computational analysis suggested that the novel identified missense mutation could affect ATP binding pattern and ATM protein flexibility, while Alu element insertion could probably induces a premature stop codon. Furthermore, our results confirm the pathogenic effect of identified splicing mutations on the ATM transcript. Moreover, we noticed a high percentage of LTCD4 + and LTCD8 + senescent subsets in AT patients and a relative increase of the of intermediate and non-classical monocytes accompanied with a decrease of classical monocytes specifically in AT patients with truncated biallelic mutations which was intriguingly similar to the immune profile of AT parents. In addition, a difference of immune pattern was observed between AT patients with biallelic truncated mutations compared to those with at least one non-truncated mutation, with a variability intragroup. Gene expression analysis identified FOXO3, IL33 and METTL3 as putative genes that may yield clues into AT pathogenesis. Conclusion Taken together, our study expands the mutational spectrum of AT disease worldwide and further characterize the immune profile of AT patients uncovering a possible difference in some immune cellular subsets related to ATM mutation type and delineate putative immune abnormalities related to ATM heterozygosity among AT parents. Furthermore, dysregulation in FOXO3, IL33 and METTL3 expression could be related to disease severity.
2026-01-23 | Phenotypic characterization and cancer risk related to homozygous and heterozygous mutations in the ataxia-telangiectasia mutated gene
The ataxia-telangiectasia mutated (ATM) gene plays a critical role in DNA damage repair and functions as a tumor suppressor. Homozygous mutations in the ATM gene cause ataxia-telangiectasia (A-T), a rare autosomal recessive disorder characterized by progressive neurodegeneration, immunodeficiency, radiosensitivity, and a markedly increased risk of malignancy. In contrast, individuals carrying heterozygous ATM mutations are phenotypically normal but demonstrate an elevated susceptibility to cancer, particularly breast cancer. This review aimed to summarize current knowledge on the phenotypic manifestations associated with both homozygous and heterozygous ATM mutations and evaluate their relationship to cancer risk. A total of 98 published studies were reviewed, alongside data from established genetic databases including OMIM, GeneCards, UniProt, and GeneReviews. Evidence indicated that A-T patients with homozygous ATM mutations are at high risk for malignancies, with lymphoid cancers such as leukemia and lymphoma predominating in individuals under 20 years of age, while solid tumors are more frequently observed in adults. Heterozygous ATM mutation carriers exhibited a significantly increased risk of cancer, most notably breast cancer, with emerging data suggesting elevated risk in males as well. Further large-scale and longitudinal studies are required to more precisely quantify cancer risk associated with ATM mutations and to improve surveillance, genetic counselling, and clinical management strategies.
2025-12-30 | Variant ataxia-telangiectasia presenting as tremor-dystonia syndrome in a bulgarian religious minority
Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder due to mutations in the ATM-gene. Given the residual kinase activity and the type of ATM mutation, its clinical spectrum is varying from a severe classic phenotype to a variant atypical form.The study included 28 patients, belonging to four big Bulgarian Muslim pedigrees with tremor and dystonia. Whole exome sequencing was performed in 7 affected from 2 unrelated pedigrees, followed by Sanger sequencing of the coding sequences and exon/intron borders of the ATM gene.Twenty four of the affected were homozygous for c.8147T>C (p.Val2716Ala) in ATM, while four of the affected were compound heterozygous. The targeted Sanger sequencing along the ATM gene revealed as a second mutation in three of them the splice-site variant c.4909+1G>A and in one patient a synonymous pathogenic variant with splicing effect c.3576G>A, p.Lys1192. The age at onset in our group varies between 14 days and 40 years. The main symptoms are dystona and tremor, more prominent in the upper limbs and the neck, dystonic dysarthria and dysphagia. The clinical course was very slowly progressive. Brain imaging was normal in the majority of them.Clinical features, due to mutations in ATM gene can be very broad. The disease may appear as dystonia, especially of early onset, without frank cerebellar involvement and also normal cerebral imaging. A-T should be considered in all patients with unexplained, even mild movement disorders and elevated alpha fetoprotein.
oligonucleotides
2026-03-12 | Interferon stimulatory DNA activates the DNA damage signaling through ATM and DNA-PK sensing.
In eukaryotic cells, DNA is normally confined in the nucleus and mitochondria and the presence of DNA in the cytoplasm is a danger signal that activates innate immune responses. Upon detection of cytoplasmic dsDNA in mammalian cells, the cGAS-STING pathway induces type I-Interferon and inflammatory responses, a key step in innate immune activation. Since its discovery, Interferon Stimulatory DNA (ISD), a linear double-stranded DNA, has been largely used to study the cGAS-STING pathway and its regulation. Here, we show that ISD also stimulates DNA damage signaling. We show that ISD activates both ataxia telangiectasia mutated and DNA-dependent protein kinase, the sensor kinases of the DNA damage response, independently of cGAS-STING signaling. Our results demonstrate that the DNA damage response, which is usually considered a response to genomic DNA lesions, can be promoted by foreign DNA. Our data further suggest that ISDs coordinate two central protective functions of cells, the innate immunity and DNA damage checkpoints.
2025-10-29 | Lets talk about ataxia-telangiectasia: Meeting report of the AT clinical research conference June 2025.
Almost fifty years after the identification of ataxia telangiectasia (A-T) as a radiosensitive disorder and thirty years following the identification of ataxia telangiectasia mutated (ATM) as the defective gene, clinicians and scientists gathered at Loughborough University, UK from June 25th -27th 2025 for an Ataxia Telangiectasia Clinical Research Conference. The mix of expertise of clinicians and scientists with basic and translational expertise ensured that a focus was on how to exploit our knowledge of ATM's function to clinical benefit. Considerable emphasis was placed on the role of ATM in the DNA damage response and the consequences in this multisystem disease, including the neurodegenerative phenotype. The increasingly recognized role of ATM in oxidative stress was also considered and how it was pertinent to mitochondrial dysfunction, metabolic abnormalities and energy metabolism in A-T. The implications of these roles of ATM in protecting the genome/cell and the development of new technology, such as organoids, were widely discussed in the clinical setting of patients with A-T. An important contribution to the meeting was the description of pathways /mechanisms that have led to the development of therapeutic approaches for A-T including the use of specific antisense oligonucleotides to restore ATM function in patients; delivery of full-length ATM cDNA to A-T cells; eDSP (formerly EryDex) that encapsulates dexamethasone sodium phosphate in a patient's own red blood cells and the use of small molecules (triheptanoin, nicotinamide riboside and N-acetyl leucine) to correct mitochondrial and metabolic function.
2025-08-09 | Impact of specific productivity and operation mode upon the biophysical properties of HIV-1 Gag-based virus-like particles.
Virus-like particles (VLPs) are non-infective vaccine candidates that have gained interest given their natural ability to elicit strong immune responses. Particularly, HIV-1 Gag-based VLPs are one of the most described platforms for vaccine development, provided their ability for successful pseudotyping either by genetic engineering or click chemistry. When Gag polyprotein is recombinantly expressed, VLPs are naturally assembled in the vicinity of the cell membrane and then secreted by cell budding, taking part of the host cell membrane. Their properties are dependent upon the cell line and manufacturing method. Although great advancements toward the implementation of analytical methods have been made, VLP quality attributes are quite unclear whenever production is enhanced by metabolic engineering or process intensification strategies. This work offers a comparative study of VLP quality attributes upon transient gene expression (TGE) in HEK293 cell cultures operated in batch and perfusion mode. Moreover, the impact of specific productivity is also studied by ataxia telangiectasia mutated (ATM) gene silencing, which has been reported to enhance fourfold VLP production. A linear negative correlation was found between the ratio of Gag monomers/VLP and specific productivity. 3100 ± 100 monomers/VLP were obtained for the standard batch production, dropping to 1900 ± 100 and 800 ± 60 for the perfusion and batch ATM-knockdown conditions, respectively. Furthermore, functionalization rates were measured in terms of Cy5 per total particles (TP). Both perfusion-derived nanoparticles achieved functionalization rates of 2800 Cy5/TP. On the contrary, those nanoparticles produced in batch yielded functionalization rates below 1000 Cy5/TP. Moreover, a complete lipidome analysis revealed a relative decrease in the quantity of lipid/particle for all studied conditions in comparison to the standard batch production. Finally, all VLP samples were characterized to assess the impact of the differential physicochemical properties upon purification and stability rates. KEY POINTS: • VLP quality inversely correlates with Gag-specific productivity and operation mode. • Functionalization and lipid content drop with metabolic burden or ATM silencing. • Perfusion enables high VLP recovery and lyophilization with preserved morphology.
2025-01-03 | Targeted knockdown of ATM, ATR, and PDEδ increases Gag HIV-1 VLP production in HEK293 cells.
Several strategies have been developed in recent years to improve virus-like particle (VLP)-based vaccine production processes. Among these, the metabolic engineering of cell lines has been one of the most promising approaches. Based on previous work and a proteomic analysis of HEK293 cells producing Human Immunodeficiency Virus-1 (HIV-1) Gag VLPs under transient transfection, four proteins susceptible of enhancing VLP production were identified: ataxia telangiectasia mutated (ATM), ataxia telangiectasia and rad3-related (ATR), DNA-dependent protein kinase catalytic subunit (DNA-PKcs), and retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta (PDEδ). The knockdown of ATM, ATR, and PDEδ in HEK293 cells increased HIV-1 VLP titers in the supernatant by 3.4-, 2.1-, and 2.2-fold, respectively. Also, possible metabolic synergies between plasmids were investigated by statistical design of experiments (DoE), enabling us to identify the optimal production strategy, that was further demonstrated at lab-scale stirred tank bioreactor operated in perfusion, significantly increasing both VLPs specific and volumetric productivities to 8.3 × 103 VLPs/cellxday and 7.5 × 1012 VLPs/Lxday, respectively. KEY POINTS: • ATM, ATR, and PDEδ knockdowns increased VLP production in HEK293 cells. • Knockdown of ATM increased budding efficiency and extracellular vesicle concentration. • ATM knockdown could be intensified to bioreactor scale operated in perfusion.
2024-08-07 | The importance of synthetic pharmacotherapy for recessive cerebellar ataxias.
The last decade has witnessed major breakthroughs in identifying novel genetic causes of hereditary ataxias, deepening our understanding of disease mechanisms, and developing therapies for these debilitating disorders. This article reviews the currently approved and most promising candidate pharmacotherapies in relation to the known disease mechanisms of the most prevalent autosomal recessive ataxias. Omaveloxolone is an Nrf2 activator that increases antioxidant defense and was recently approved for treatment of Friedreich ataxia. Its therapeutic effect is modest, and further research is needed to find synergistic treatments that would halt or reverse disease progression. Promising approaches include upregulation of frataxin expression by epigenetic mechanisms, direct protein replacement, and gene replacement therapy. For ataxia-telangiectasia, promising approaches include splice-switching antisense oligonucleotides and small molecules targeting oxidative stress, inflammation, and mitochondrial function. Rare recessive ataxias for which disease-modifying therapies exist are also reviewed, emphasizing recently approved therapies. Evidence supporting the use of riluzole and acetyl-leucine in recessive ataxias is discussed. Advances in genetic therapies for other neurogenetic conditions have paved the way to implement feasible approaches with potential dramatic benefits. Particularly, as we develop effective treatments for these conditions, we may need to combine therapies, consider newborn testing for pre-symptomatic treatment, and optimize non-pharmacological approaches.
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2026-04-13 | Cell-Based Therapies for Spinocerebellar Degenerations: A Systematic Review of Human Clinical Evidence.
Spinocerebellar degenerations (SCDs) are progressive hereditary and selected sporadic cerebellar neurodegenerative disorders with limited disease-modifying options. Cell-based therapies particularly, mesenchymal stromal/stem cells (MSCs), neural stem/progenitor cells, olfactory ensheathing cells (OECs), cord blood mononuclear cells (CBMCs), and hematopoietic stem cell transplantation (HSCT) are biologically plausible candidates, but their clinical efficacy and safety remain uncertain. We searched MEDLINE/PubMed, Embase, Scopus, Web of Science, and Cochrane Library from inception to 10 October 2025 (no language restrictions). The OSF-registered protocol prespecified eligibility, outcomes, and design-specific risk-of-bias (RoB) tools, with harmonized overall RoB judgments. We included human interventional or observational reports of cell-based or cell-derived products in hereditary ataxias and selected cerebellar-predominant degenerative syndromes within the OPCA/MSA-C spectrum, and extracted clinical efficacy, safety, and follow-up. Of 603 records screened, 17 reports met the protocol-defined inclusion criteria (15 full texts; 2 abstracts; 2006–2025). Most were small, uncontrolled case series, predominantly from China. Cell types: MSCs (9/17), HSCT in ataxia-telangiectasia (3/17), OECs (3/17), and others (neural stem cells [NSCs], CBMCs; 2/17). Routes were intrathecal and/or intravenous for MSC/CBMC; OEC/NSC were intracerebral/intraspinal; HSCT was delivered intravenously. Primary follow-up was typically 1–6 months. Safety was generally acceptable for MSC/CBMC/OEC with no treatment-related deaths and mostly transient post-procedural symptoms; HSCT exhibited regimen-related toxicities consistent with conditioning intensity. Efficacy signals were modest and often transient: short-term International Cooperative Ataxia Rating Scale (ICARS) improvements were reported across multiple series. Cell-based therapies for SCDs show biological plausibility and generally reassuring short-term safety, but current human evidence, dominated by uncontrolled, high-bias studies does not establish efficacy or durability. Priority should shift to rigorously controlled trials, standardized good manufacturing practice (GMP)-characterized products, blinded centralized ratings, careful control of co-interventions, and objective biomarkers.
2025-07-19 | Neurological Complications in Inborn Errors of Immunity: A Scoping Review of Clinical Spectrum, Pathophysiological Mechanisms, and Therapeutic Strategies.
Inborn errors of immunity (IEIs) are traditionally viewed as monogenic disorders of the immune system, but mounting evidence indicates that they often have underappreciated impacts on the nervous system. We review the emerging intersection between IEIs and neurological diseases, spanning neurodevelopmental and neurodegenerative manifestations. We discuss how genetic overlaps between immunity and brain development-for example, defects in DNA repair, chromatin remodeling, or cytokine signaling-can lead to combined immunological and neurological phenotypes. Clinical data from patient cohorts highlight that a substantial subset of IEIs present with neurodevelopmental disorders (such as autism spectrum disorder, intellectual disability, or ADHD) and/or neurodegenerative diseases (such as progressive ataxia, motor regression, or cognitive decline). These comorbidities arise through diverse mechanisms, including direct roles of immune genes in neural development, the impact of chronic inflammation on the brain, and metabolic byproducts toxic to neural tissue. We illustrate these mechanisms with examples such as ataxia-telangiectasia (a DNA repair defect causing immunodeficiency and cerebellar degeneration) and DiGeorge syndrome (a developmental immunodeficiency often initially diagnosed as autism). The translational importance of these insights is profound-recognizing neurological involvement in IEIs can improve early diagnosis and multidisciplinary care, whereas a deeper understanding of immune-neural crosstalk opens avenues for novel therapies (such as targeted anti-inflammatory treatments or gene therapies that address both immune and neural dysfunction). By integrating immunology and neuroscience perspectives, this comprehensive review sheds light on the immune underpinnings of certain neurologic diseases and underscores the importance of collaborative management for patients at this complex interface.
2025-06-26 | Sarcoidosis-like Skin Lesions as the First Manifestation of Ataxia-Telangiectasia.
Ataxia-telangiectasia is a rare autosomal recessive disorder that is difficult to diagnose due to its unpredictable presentation. It is characterized by cerebellar degeneration, telangiectasias, immunodeficiency, frequent pulmonary infections, and tumors. Immune system abnormalities manifest as disruptions in both cellular and humoral immunity. The most common findings include decreased levels of immunoglobulin classes (IgA, IgM, IgG, and IgG subclasses) and a reduced number of T and B lymphocytes. A four-year-old girl was initially evaluated and treated for skin lesions that presented as crusts spreading across her body. She was monitored by a pulmonologist due to frequent bronchial obstructions. Over time, she developed bilateral scleral telangiectasia, saccadic eye movements, and impaired convergence. Her gait was wide-based and unstable, with truncal ataxia and a positive Romberg sign. Laboratory tests revealed decreased immunoglobulin G levels, subclass IgG4 levels, elevated alpha-fetoprotein, and a reduced number of T and B lymphocytes. Brain magnetic resonance imaging showed cerebellar atrophy. Whole-exome sequencing identified heterozygous variants c.1564-165del, p.(Glu5221lefsTer43), and c.7630-2A>C in the serine/threonine-protein kinase ATM (ataxia-telangiectasia mutated) gene, confirming the diagnosis of ataxia-telangiectasia. Following diagnosis, treatment with intravenous immunoglobulin replacement was initiated along with infection prevention and management. The goal of this case report is to raise awareness of the atypical initial presentation that may lead to a diagnostic delay. We emphasize the importance of considering ataxia-telangiectasia in the differential diagnosis, even when classical neurological signs are not yet evident.
2023-10-31 | Ataxia Telangiectasia in Latin America: clinical features, immunodeficiency and mortality in a multicenter study
Abstract Ataxia-telangiectasia (AT) is a rare neurodegenerative genetic disorder leading to neurological defects, telangiectasias and immunodeficiency. We aimed to study the clinical and immunological features of Latin American patients with AT and analyze the factors associated with AT-related mortality. Referral centers ( n = 46) from 9 Latin American countries participated in this retrospective cohort study. AT was defined with ESID Criteria. Designated physicians in each healthcare center reviewed medical records of 218 patients with AT. Data from 218 patients with AT were analyzed. Mean ± standard deviation ages at symptom onset and diagnosis were 1.6 ± 1.1 and 5.7 ± 3.5 years, respectively. Most (66.9%) patients presented recurrent airway infections, which was significantly associated with IgA deficiency. Humoral deficiencies included IgA deficiency in 60.8% of patients and IgG deficiency in 28.6%. Lymphopenia was present in most cases, mainly affecting T and B cells. Around half of patients used antibiotic prophylaxis (57.7%) and immunoglobulin replacement (49.1%). No complications due to live viral vaccines were reported. Their mean survival was 24.2 years and Kaplan-Meier 20-year-survival rate was 52.6%. Low IgG levels were associated with decreased life expectancy (hazard ratio 2.1; 95% CI, 1.11–3.93), whereas male sex was a protecting factor (hazard ratio 0.52; 95% CI, 0.27–0.99). There was a high frequency of recurrent infections and immunologic abnormalities in our sample of patients with AT. Higher mortality was associated with female gender and low IgG levels. These findings suggest that immunologic status should be investigated in all patients with AT, thus helping us to improve therapeutic strategies.
2023-01-24 | Successful Treatment of Large B-Cell Lymphoma in a Child with Compound Heterozygous Mutation in the ATM Gene.
Ataxia-telangiectasia (AT) is a multisystemic neurodegenerative inborn error of immunity (IEI) characterized by DNA repair defect, chromosomal instability, and hypersensitivity to ionizing radiation. Impaired DNA double-strand break repair determines a high risk of developing hematological malignancies, especially lymphoproliferative diseases. Poor response to treatment, excessive chemotherapy toxicities, and the need for avoiding exposure to ionizing radiation make the successful clinical management of patients with AT challenging for oncologists. We describe the favorable outcome of the LBCL with IRF4 rearrangement at stage III in a 7-year-old female patient diagnosed with AT. The patient was treated according to the B-HR arm of the INTER-B-NHL-COP 2010 protocol, including the administration of rituximab, cyclophosphamide, methotrexate, prednisone, etc. She presented excessive treatment toxicities despite individually reduced doses of methotrexate and cyclophosphamide. However, in the MRI there was no significant reduction in pathologic lymph nodes after three immunochemotherapy courses. Therefore, a lymph node biopsy was taken. Its subsequent histopathological examination revealed tuberculosis-like changes, though tuberculosis suspicion was excluded. After two following immunochemotherapy courses, PET-CT confirmed complete remission. From March 2022 onwards, the patient has remained in remission under the care of the outpatient children's oncology clinic.
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Drug Discovery Landscape
8 orphan drug designations for Ataxia-telangiectasia.
8 orphan drug designations for Ataxia-telangiectasia.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
3-(Aminocarbonyl)-1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-pyridinium chloride (1:1) | small molecules | EMA | 2026-06-19 | — | AdRes EU B.V. |
Nicotinamide riboside chloride | small molecules | FDA | 2024-06-03 | — | ChromaDex, Inc. |
Tempol | small molecules | FDA | 2021-07-21 | — | Matrix Biomed, Inc. |
Acetylleucine | small molecules | EMA | 2019-01-11 | — | IntraBio Ireland Ltd |
N-Acetyl-Leucine | small molecules | FDA | 2018-10-02 | — | IntraBio Inc. |
betamethasone | small molecules | FDA | 2015-10-07 | — | Acasti Pharma Inc. |
DEXAMETHASONE SODIUM PHOSPHATE ENCAPSULATED IN HUMAN AUTOLOGOUS ERYTHROCYTES [EryDex System] | cell therapies | EMA | 2013-07-17 | — | Quince Therapeutics S.p.A. |
dexamethasone sodium phosphate encapsulated in autologous erythrocytes | cell therapies | FDA | 2012-07-24 | — | Quince Therapeutics, S.p.A. |
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