small molecules

2026-09-28 | ATM safeguards DNA replication by restraining pathological repriming at endogenous base lesions.

Poly(ADP-ribose) polymerase inhibitors (PARPi) exploit homologous recombination (HR) deficiency in BRCA1/2-mutant cancers to induce synthetic lethality. PARPi also kill ataxia telangiectasia-mutated (ATM)-deficient cells, but the underlying mechanism has remained unclear. Here, we define the mechanism of PARPi cytotoxicity in mammalian ATM-deficient cells, uncovering a critical role for ATM in DNA replication. In the absence of ATM, unrestrained PRIMPOL-dependent repriming at oxidative base lesions generates post-replicative DNA gaps that activate PARP. This defect is driven by aberrant BRCA1-A recruitment to stalled replication forks in ATM-deficient cells, suppressing HLTF/ZRANB3-mediated replication fork slowing. These DNA gaps require HR for repair and underlie PARPi synthetic lethality. Suppressing repriming or base excision repair, or reducing oxidative stress, alleviates these defects. Our findings reveal how spontaneous oxidative DNA damage synergizes with dysregulated replication to drive PARPi sensitivity, establishing a paradigm of post-replicative repair addiction in ATM-deficient cells and linking oxidative DNA damage to genome instability in ataxia telangiectasia.

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2026-09-26 | Expanding Synthetic Lethality in DNA Damage Response-Defective Cancers Through Stress Phenotype-Guided Kinase Targeting.

Synthetic lethality has reshaped oncology, particularly in tumours with defects in DNA damage response (DDR) pathways, yet therapeutic strategies centred on canonical DDR targets, including poly(ADP-ribose) polymerase (PARP), ataxia telangiectasia and Rad3-related protein (ATR), checkpoint kinase 1 (CHK1) and Wee1 G2 checkpoint kinase (WEE1), remain constrained by resistance, toxicity and biological heterogeneity of DDR alterations. Emerging evidence indicates that DDR deficiency extends beyond impaired DNA repair to generate interconnected stress phenotypes involving replication fork instability, chromosomal instability, transcriptional and cell-cycle dysregulation, oxidative/proteotoxic stress and metabolic imbalance. These states may increase tumour-cell reliance on kinases that are not canonical DNA repair enzymes or proximal DDR sensors, here referred to as non-canonical DDR-associated kinases. In this review, we examine the mechanistic rationale and translational potential of targeting kinases that regulate mitosis, transcriptional adaptation, checkpoint signalling, stress responses and metabolic homeostasis in DDR-defective tumours. We distinguish kinase dependencies supported by direct DDR-context-specific vulnerability or PARP inhibitor sensitisation from those whose relevance remains primarily mechanistic or hypothesis-generating and propose a shift from genotype-based patient selection toward functional stress phenotyping that integrates DNA repair capacity with replication stress, chromosomal instability, transcriptional conflict and the metabolic state. Finally, we evaluate pharmacological strategies, including rational combinations, allosteric modulation, polypharmacology and targeted protein degradation, and highlight the need for biomarker-guided clinical translation.

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2026-09-11 | Phase 1a Clinical Trial of XRD-0394, a First-in-Class Dual Ataxia-Telangiectasia Mutated and DNA-Dependent Protein Kinase Inhibitor, in Combination With Palliative Radiation Therapy.

XRD-0394 is a dual ataxia-telangiectasia mutated and DNA-dependent protein kinase inhibitor designed to increase tumor radiosensitivity. We evaluated the safety, pharmacokinetics, and pharmacodynamics of single-dose XRD-0394 administered with palliative radiation therapy (RT) in a first-in-human trial. In an open-label, multicenter phase 1a dose-escalation study, XRD-0394 (40, 80, or 160 mg) was given once, 90 ± 30 minutes before fraction 2 of palliative RT. Primary endpoints were dose-limiting toxicities and tolerability; a coprimary objective was achieving a prespecified plasma exposure target (≥530 ng/mL [1 µM] at 1-4 hours postdose). Exploratory pharmacodynamic activity was assessed by phosphorylated KRAB-associated protein 1 immunohistochemistry in tumor biopsies. Twelve participants were treated. No dose-limiting toxicities occurred and the maximum tolerated dose was not reached. Treatment-related adverse events were limited to grade 1 nausea and diarrhea (n = 2), with no treatment-related serious adverse events. At 160 mg, exposures met the prespecified target and supported selection for further development. Single-dose XRD-0394 can be safely combined with palliative RT at plasma exposures that exceeded the prespecified target threshold, supporting fractionated multidose studies.

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2026-09-06 | Insights Into the Mechanisms of Biological Aging That Guide Translational and Clinical Research.

Understanding the molecular mechanisms of aging guides the development of prevention, intervention, and treatment strategies to reduce the incidence of common age-associated diseases. Over the past decades, the proposed key features (hallmarks) of aging cells have directly or indirectly provided us clues, furthering our understanding of the causes of disease and assisting with the development of therapeutic strategies for diseases such as rare premature aging diseases like Werner syndrome and ataxia telangiectasia (A-T), as well as the common age-related diseases like dementia and sarcopenia. In this editorial, we take a closer look at three of these hallmarks including genomic instability, defective macroautophagy, and mitochondrial dysfunction, and the applications of these concepts in understanding the progress of complex diseases. Mounting studies from the laboratory, supported by emerging clinical evidence, point to the reduction of the oxidized form of nicotinamide adenine dinucleotide (NAD+) as a commonality between many of these hallmarks of aging. Intriguingly, stimulating mitochondrial autophagy (mitophagy) via improvement of NAD+ availability appears to be a promising and effective therapeutic strategy for many diseases relating to aging. Future studies on the hallmarks of aging should address their internal linkages and clinical interventions.

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2026-09-02 | An overview of the DNA damage response in female reproductive system and breast cancers: A narrative review.

The DNA damage response (DDR) is a fundamental cellular network that preserves genomic integrity, and its dysregulation drives initiation, progression, and therapeutic response in female reproductive system and breast cancers. This narrative review provides a comparative analysis of DDR alterations across ovarian, endometrial, cervical, and breast cancers, synthesizing molecular studies, clinical trials, and international guidelines from PubMed/MEDLINE, Scopus, and Web of Science. DDR alterations vary substantially among these cancers, reflecting differences in tissue origin, hormonal regulation, and viral oncogenesis. Homologous recombination repair defects, particularly in breast cancer susceptibility 1/2, partner and localizer of BRCA2, ataxia telangiectasia mutated, and checkpoint kinase 2), are prevalent in ovarian, endometrial, and breast cancers, predicting sensitivity to platinum-based chemotherapy and poly (ADP-ribose) polymerase inhibitors. In endometrial cancer, homologous recombination deficiency predominates in high-grade tumor protein p53-mutated subtypes, while Fanconi anemia pathway alterations characterize aggressive serous carcinomas. Cervical cancer exhibits virus-induced DDR disruption and replication stress. Quantitative biomarkers, including tumor mutational burden, microsatellite instability, Radiation sensitive 51, Fanconi anemia complementation group D2, excision repair cross-complementation group 1, and DDR-related microRNAs enable patient stratification. Emerging ataxia telangiectasia and Rad3-related and WEE1 inhibitors show promise in combination regimens. Understanding of tumor-specific DDR enables rational therapeutic stratification, providing a framework for precision oncology.

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proteins

2026-09-26 | Proteomics in Ataxia Telangiectasia Fibroblasts Revealed Disease Hallmarks Recovered by ATM Variants.

Ataxia-telangiectasia (A-T) is a multisystemic genetic disorder caused by pathogenic mutations in the ATM gene, with effects extending beyond the canonical DNA damage response. We investigated whether two compact ATM transcript variants, ATM 4-53 (exons 4 and 53 joined) and ATM SINT (an in silico-designed ATM variant), could rescue disease associated with cellular alterations and inform construct selection for future delivery strategies. A-T fibroblasts transduced with either ATM variants or an empty vector were compared with wild-type fibroblasts using complementary label-free and tandem mass tag-based quantitative proteomics. Bioinformatic pathway and network analyses were integrated with biochemical and functional validation assays. A-T fibroblasts displayed coordinated alterations in proteostasis, proteasome function, RNA processing pathways, interferon-associated signaling, extracellular matrix organization, cell migration, and nanomechanical properties. Expression of both ATM variants partially or extensively reversed these abnormalities, restoring protein folding and proteasomal components, reducing protein aggregation, attenuating inflammatory signaling, and normalizing extracellular matrix-related phenotypes. ATM SINT generally produced the broader and more consistent rescue, particularly for proteostasis and RNA processing-associated networks. These findings show that compact ATM variants can recover multiple non canonical ATM dependent cellular functions in A-T fibroblasts and identify ATM SINT as the more effective construct in this model. Proteomic profiling combined with orthogonal functional validation may therefore support rational selection of ATM variants for subsequent preclinical delivery studies.

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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.

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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.

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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.

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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.

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gene therapies

2026-04-09 | Clinical and therapeutic impact of newborn screening-based early detection of ataxia-telangiectasia.

Not available.

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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.

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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.

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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.

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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.

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oligonucleotides

2026-09-11 | Novel and Emerging Therapies for Childhood-Onset Movement Disorders.

Childhood-onset movement disorders comprise a heterogeneous group of rare conditions with substantial unmet therapeutic needs. Recent advances in disease gene discovery, mechanistic modeling, and translational platforms have accelerated the development of targeted therapies and enabled innovative clinical trial designs for small patient populations. To review novel and emerging therapies for childhood-onset movement disorders, with a focus on pharmacologic strategies, disease-modifying approaches, and patient-centered precision therapies. We surveyed the literature, major conference proceedings, and expert networks to identify therapies approved, in clinical development, or supported by compelling preclinical data between 2022 and 2025. We focused on small molecules and genetic therapies for conditions in which movement disorders represent a prominent clinical feature. Small molecules were categorized as repurposed or novel drugs, whereas genetic therapies included gene replacement, gene editing, and RNA-based expression modulation. Drug repurposing approaches have shown promise in disorders related to the GNAO1, ATP1A3, ATM, and ADCY5 genes. Novel small molecules have advanced for Friedreich's ataxia and Tourette's syndrome. Gene replacement therapies have demonstrated clinical benefit in select neurotransmitter disorders, whereas gene editing strategies have entered preclinical development for ATP1A3-related disease. Antisense oligonucleotide therapies have yielded encouraging early results across several conditions with prominent movement disorder phenotypes, including KIF1A-related neurological disorder, Angelman syndrome, SCN2A-related neurodevelopmental disorder, and ataxia-telangiectasia. Precision-based therapeutic strategies are rapidly reshaping the treatment landscape for childhood-onset movement disorders. Continued progress will depend on rigorous phenotyping, careful ethical oversight, and deliberate efforts to promote equitable global access to emerging therapies. © 2026 International Parkinson and Movement Disorder Society.

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2026-08-27 | Recent Advances in Therapy for the Neurodegenerative Disorder Ataxia-Telangiectasia.

At present, there is no cure for the human genetic disorder ataxia-telangiectasia (A-T), which is managed by supportive care. This disorder arises due to mutations in the ATM (ataxia-telangiectasia mutated) gene and is characterised by a defect in the response to DNA damage, oxidative stress, mitochondrial dysfunction and immune deficiency. The ATM protein is activated by DNA damage, reactive oxygen species (ROS), and a variety of other stimuli, which leads to the phosphorylation or altered cellular localisation of multiple protein substrates that participate in cellular defence pathways. ATM plays a central role in orchestrating cellular defence against stress, which forms a focal point for approaches to treating the symptoms in this disorder. These strategies involve boosting mitochondrial function and dampening the inflammatory response. A more direct approach to treatment is gene therapy, yet the leading method using Adeno-Associated Virus (AAV) is hampered by the large size of the ATM gene itself. The use of antisense oligonucleotides (ASO) as an alternative gene therapeutic approach to treat patients has been increasingly utilised. However, only certain mutations fit the criteria for ASO-based intervention, which encourages rescue through readthrough of premature truncation mutations. For this reason, small-molecule-based therapies addressing the multi-system nature of the disease are urgently required. We address these different approaches to therapy and the outcome of numerous recent clinical trials with A-T patients, as well as ongoing research that has potential to lead to therapy.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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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