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:
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.
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.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
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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