RARE DISEASE
Cockayne syndrome
Cockayne syndrome
Cockayne syndrome
Drug discovery
2
drugs
With orphan designations
Overview
Cockayne syndrome is a rare autosomal recessive disorder caused by mutations in ERCC6 or ERCC8 genes, leading to defective DNA repair. Key features include growth failure, microcephaly, photosensitivity, sensorineural hearing loss, progressive neurodegeneration, and premature aging. Diagnosis involves genetic testing for biallelic pathogenic variants. Prognosis is poor, with multisystem deterioration and reduced lifespan [1][6][12].
Burden
Morbidity: Progressive motor/sensory decline, intellectual disability, and organ dysfunction requiring lifelong care [6][12][16].
Mortality: Median survival ranges from 5–12 years (type II) to 10–20 years (type I); type III has variable severity [6][12][17].
Psychosocial impact: High caregiver burden, limited access to specialized care, and financial strain due to adaptive equipment/therapies [14][17].
Therapies
Supportive care: Multidisciplinary management (neurology, audiology, ophthalmology, nutrition) and symptom-specific interventions (hearing aids, UV protection, gastrostomy for dysphagia) [6][13][16].
Avoidance of metronidazole due to risk of hepatotoxicity [6][12].
Emerging therapies: Preclinical gene replacement (AAV9 vectors in CSA/XPA mice) and drug repurposing screens targeting neurodegeneration [3][8].
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare neoplastic diseases, rare neurological diseases, rare ophthalmic disorders, rare otorhinolaryngological diseases, rare skin diseases
Research Papers
202 drug discovery papers about Cockayne syndrome, with 1 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
202 drug discovery papers about Cockayne syndrome, with 1 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-31 | Pediatric Ocular Abnormalities: A Pictorial Review of Genetic, Metabolic, and Syndromic Associations. Part 1: Abnormalities of the Globe and Lens
SUMMARY:
This 2-part pictorial review illustrates the spectrum of ocular abnormalities in pediatric imaging and highlights their diagnostic and prognostic implications. Part 1 focuses on globe and lens abnormalities, including the microphthalmos-anophthalmos-coloboma (MAC) complex, macrophthalmos, congenital cataracts, and lens dislocation. Part 2 covers posterior segment and optic pathway abnormalities, ranging from persistent fetal vasculature to optic nerve pathologies. Selected cases demonstrate key associated brain and spine imaging features, syndromic associations, and prognostic significance, showing how orbital imaging can guide targeted genetic testing, improve diagnostic accuracy, and differentiate overlapping conditions. By systematically evaluating the orbits on pediatric brain MRI, radiologists can identify genetic disorders and syndromes early, support clinical and genetic assessment, and improve patient care.
Abbreviations
CHARGE: coloboma of the eye, heart defects, atresia of the choanae, retardation of growth and/or development, genital and/or urinary abnormalities, and ear abnormalities and deafness CIMDAG: cerebellar hypoplasia and cataracts, intellectual disability, congenital microcephaly, dystonia and dyserythropoietic anemia, and growth retardation CS: Cockayne syndrome COACH syndrome: cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, hepatic fibrosis ECCL: encephalocraniocutaneous lipomatosis FCMD: Fukuyama congenital muscular dystrophy JS: Joubert syndrome MAC: microphthalmos-anophthalmos-coloboma MEB: muscle-eye-brain disease MGDA: morning glory disc anomaly OAVS: oculo-auriculo-vertebral spectrum OCCS: oculocerebrocutaneous syndrome PBS: Poretti-Boltshauser syndrome TORCH: toxoplasmosis, other agents (such as HIV, syphilis, and Zika), rubella, cytomegalovirus, and herpes simplex virus WMS: Weill-Marchesani syndrome WWS: Walker-Warburg syndrome
2026-07-30 | AAV-mediated gene therapy demonstrates phenotypic rescue in a mouse model of Cockayne Syndrome.
Cockayne Syndrome (CS) is an autosomal recessive, progressive developmental and neurodegenerative disease. Approximately 30% of cases are caused by mutations in the ERCC8/CSA gene. Patients with CS present with cutaneous photosensitivity, growth failure, shorter life span, and a progressive degeneration of the central nervous system. Loss-of-function mutations in CSA result in deficiencies in the transcription-coupled nucleotide excision repair (TC-NER). Currently, no therapies are available for these patients. Adeno-associated virus (AAV)-mediated gene therapy offers an opportunity to address this unmet need. We designed a new AAV vector encoding human CSA under a ubiquitous promoter. We tested the therapeutic efficacy of this AAV9-CSA vector by neonatal intracerebroventicular injection in the Csa-/-;Xpa-/- mouse model. Treatment with AAV9-CSA resulted in a significant increase in lifespan, and broad distribution of human CSA in the brain and heart, without evidence of vector-related toxicity. Despite clear therapeutic benefit, we also observed neuroradiological abnormalities, and neuropathologic alterations, including hypomyelination, astrocytosis, and microgliosis, as well as likely life-limiting transcriptomic alterations in liver at endpoint. Nonetheless, the success of these experiments paves the way for the first clinical translation of an AAV gene therapy for CS patients into humans.
2026-07-15 | Recognition of multimolecular G-quadruplex regulates phase separation of cockayne syndrome B.
Cockayne syndrome B (CSB) is a multifaceted protein with known functions in DNA repair and transcription elongation. We recently demonstrated that CSB can recognize DNA secondary structures known as multimolecular G4s (mG4s) with high selectivity, but the potential biological significance of this interaction remains to be elucidated. In this study, we report that CSB can undergo liquid-liquid phase separation (LLPS), a process heavily linked with transcriptional regulation. Importantly, we found that the binding of CSB to mG4s promotes LLPS, leading to the physical segregation of DNA sequences containing mG4s within CSB-mG4 droplets from those lacking this structural motif. Furthermore, we revealed that mG4-binding alters the physicochemical properties of the phase-separated CSB, including increased salt resistance and decreased in-droplet mobility. Given the growing evidence supporting an active role for G4s in stimulating transcription, we anticipate that the selective LLPS displayed by CSB upon mG4 binding may be relevant in the context of transcriptional regulation.
2026-06-03 | Targeting the Mitochondrial Phenotype in Cockayne Syndrome Patient Cells: From Bioenergetic Fragility to Pharmacologic Rescue.
Cockayne syndrome (CS), primarily caused by autosomal recessive pathogenic variants in ERCC6 (CSB) or ERCC8 (CSA), is a transcription-coupled nucleotide excision repair disorder. CS frequently presents with features similar to primary mitochondrial disease (PMD), including leukodystrophy, lactic acidemia, and skeletal muscle mitochondrial DNA (mtDNA) depletion. How this mitochondrial phenotype arises at the cellular level, and whether it can be pharmacologically targeted, is not yet clear. We characterized mtDNA content, respiratory chain (RC) protein abundance, mitochondrial biogenesis signaling pathways, and oxidative phosphorylation capacity in primary fibroblasts from two siblings with identical compound heterozygous ERCC6 pathogenic variants (c.1526+1G>T; c.2800C>A, p.Pro934Thr) despite marked intrafamilial phenotypic divergence. A combined metabolic stress exposure (galactose, reduced glutamine, and buthionine sulfoximine, (BSO)) which reduced CS cell survival was used to screen for therapeutic leads among twenty-three candidate mitochondrial disease therapeutic compounds. Lead compounds were mechanistically validated at the level of mitochondrial superoxide, total cellular oxidative stress, glutathione, and autophagic flux. Patient fibroblasts exhibited several hallmarks of PMD, including reduced mtDNA content, decreased expression of complex I subunit NDUFB8, elevated expression of TOM20 with paradoxically decreased PGC1α suggestive of impaired mitophagic clearance, and decreased mitochondrial respiratory capacity. Under combined metabolic stress, ATP-levels indicative of survival in CS patient fibroblasts selectively collapsed to ~20% of controls. Five dual-rescue compounds, defined as agents that reproducibly restored ATP-based cell survival in both patient fibroblast lines under stress, were identified, including N-acetylcysteine (NAC), coenzyme Q10 (CoQ10), rapamycin, taurine, and (-)-epicatechin. Mechanistic profiling resolved three functional classes of therapeutic effects in CS cells: (1) upstream mitochondrial reactive oxygen species reduction (NAC, CoQ10); (2) mTORC1 inhibition bypassing defective stress-induced autophagic induction (rapamycin); and (3) extra-mitochondrial improvement in cellular stress resilience ((-)- epicatechin, taurine). ERCC6-based CSB deficiency produced a stress-sensitive and physiologically complex mitochondrial phenotype in patient fibroblasts that was pharmacologically treatable by targeting three mechanistically distinct pathways. Oxidative and broader stress buffering, autophagy modulation via mTORC1 inhibition, and enhanced cellular resilience highlight novel therapeutic opportunities to be advanced to clinical trials in CSB patients.
2026-05-20 | Transcription-coupled nucleotide excision repair protects against genomic instability and cell death induced by the liver toxin methyleugenol.
Methyleugenol (ME) is a hepatotoxic phenylpropene naturally present in various herbs and spices. Following dietary exposure, ME undergoes metabolic activation in the liver, resulting in the formation of DNA adducts and liver damage. Although ME is a suspected human liver carcinogen, it is still unknown which DNA repair pathway removes the ME-induced DNA adducts. Here, we studied the relevance of nucleotide excision repair (NER) using various genetically engineered cell models. Our data show a crucial role for transcription-coupled (TC)-NER rather than global genome (GG)-NER, revealing that ME-induced DNA damage triggers detrimental transcription stress. Mechanistically, ME-derived DNA adducts stall RNA polymerase II (RNAPII), resulting in the chromatin release and cytoplasmic export of its active subunit RPB1, followed by proteasomal degradation to allow for repair and transcription recovery. Blocking of RNAPII by ME-derived DNA lesions promotes CSB immobilization and recruitment of CSA and UVSSA. The triggered canonical TC-NER pathway removes the ME-induced DNA lesions, preserves genome integrity and promotes cell survival. At high DNA adduct levels or in cells with deficient TC-NER, persistent transcription stress provokes genomic instability, induces apoptotic cell death and strongly reduces long-term cell survival. In contrast to that, GG-NER-compromised cells are not sensitized to ME-triggered cytotoxicity. Taken together, the canonical TC-NER pathway is crucial for the repair of DNA adducts induced by ME and likely also structurally related phenylpropenes. These findings are particularly important for Cockayne syndrome patients with defective TC-NER.
2026-07-31 | Pediatric Ocular Abnormalities: A Pictorial Review of Genetic, Metabolic, and Syndromic Associations. Part 1: Abnormalities of the Globe and Lens
SUMMARY:
This 2-part pictorial review illustrates the spectrum of ocular abnormalities in pediatric imaging and highlights their diagnostic and prognostic implications. Part 1 focuses on globe and lens abnormalities, including the microphthalmos-anophthalmos-coloboma (MAC) complex, macrophthalmos, congenital cataracts, and lens dislocation. Part 2 covers posterior segment and optic pathway abnormalities, ranging from persistent fetal vasculature to optic nerve pathologies. Selected cases demonstrate key associated brain and spine imaging features, syndromic associations, and prognostic significance, showing how orbital imaging can guide targeted genetic testing, improve diagnostic accuracy, and differentiate overlapping conditions. By systematically evaluating the orbits on pediatric brain MRI, radiologists can identify genetic disorders and syndromes early, support clinical and genetic assessment, and improve patient care.
Abbreviations
CHARGE: coloboma of the eye, heart defects, atresia of the choanae, retardation of growth and/or development, genital and/or urinary abnormalities, and ear abnormalities and deafness CIMDAG: cerebellar hypoplasia and cataracts, intellectual disability, congenital microcephaly, dystonia and dyserythropoietic anemia, and growth retardation CS: Cockayne syndrome COACH syndrome: cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, hepatic fibrosis ECCL: encephalocraniocutaneous lipomatosis FCMD: Fukuyama congenital muscular dystrophy JS: Joubert syndrome MAC: microphthalmos-anophthalmos-coloboma MEB: muscle-eye-brain disease MGDA: morning glory disc anomaly OAVS: oculo-auriculo-vertebral spectrum OCCS: oculocerebrocutaneous syndrome PBS: Poretti-Boltshauser syndrome TORCH: toxoplasmosis, other agents (such as HIV, syphilis, and Zika), rubella, cytomegalovirus, and herpes simplex virus WMS: Weill-Marchesani syndrome WWS: Walker-Warburg syndrome
2026-07-30 | AAV-mediated gene therapy demonstrates phenotypic rescue in a mouse model of Cockayne Syndrome.
Cockayne Syndrome (CS) is an autosomal recessive, progressive developmental and neurodegenerative disease. Approximately 30% of cases are caused by mutations in the ERCC8/CSA gene. Patients with CS present with cutaneous photosensitivity, growth failure, shorter life span, and a progressive degeneration of the central nervous system. Loss-of-function mutations in CSA result in deficiencies in the transcription-coupled nucleotide excision repair (TC-NER). Currently, no therapies are available for these patients. Adeno-associated virus (AAV)-mediated gene therapy offers an opportunity to address this unmet need. We designed a new AAV vector encoding human CSA under a ubiquitous promoter. We tested the therapeutic efficacy of this AAV9-CSA vector by neonatal intracerebroventicular injection in the Csa-/-;Xpa-/- mouse model. Treatment with AAV9-CSA resulted in a significant increase in lifespan, and broad distribution of human CSA in the brain and heart, without evidence of vector-related toxicity. Despite clear therapeutic benefit, we also observed neuroradiological abnormalities, and neuropathologic alterations, including hypomyelination, astrocytosis, and microgliosis, as well as likely life-limiting transcriptomic alterations in liver at endpoint. Nonetheless, the success of these experiments paves the way for the first clinical translation of an AAV gene therapy for CS patients into humans.
2026-07-15 | Recognition of multimolecular G-quadruplex regulates phase separation of cockayne syndrome B.
Cockayne syndrome B (CSB) is a multifaceted protein with known functions in DNA repair and transcription elongation. We recently demonstrated that CSB can recognize DNA secondary structures known as multimolecular G4s (mG4s) with high selectivity, but the potential biological significance of this interaction remains to be elucidated. In this study, we report that CSB can undergo liquid-liquid phase separation (LLPS), a process heavily linked with transcriptional regulation. Importantly, we found that the binding of CSB to mG4s promotes LLPS, leading to the physical segregation of DNA sequences containing mG4s within CSB-mG4 droplets from those lacking this structural motif. Furthermore, we revealed that mG4-binding alters the physicochemical properties of the phase-separated CSB, including increased salt resistance and decreased in-droplet mobility. Given the growing evidence supporting an active role for G4s in stimulating transcription, we anticipate that the selective LLPS displayed by CSB upon mG4 binding may be relevant in the context of transcriptional regulation.
2026-06-03 | Targeting the Mitochondrial Phenotype in Cockayne Syndrome Patient Cells: From Bioenergetic Fragility to Pharmacologic Rescue.
Cockayne syndrome (CS), primarily caused by autosomal recessive pathogenic variants in ERCC6 (CSB) or ERCC8 (CSA), is a transcription-coupled nucleotide excision repair disorder. CS frequently presents with features similar to primary mitochondrial disease (PMD), including leukodystrophy, lactic acidemia, and skeletal muscle mitochondrial DNA (mtDNA) depletion. How this mitochondrial phenotype arises at the cellular level, and whether it can be pharmacologically targeted, is not yet clear. We characterized mtDNA content, respiratory chain (RC) protein abundance, mitochondrial biogenesis signaling pathways, and oxidative phosphorylation capacity in primary fibroblasts from two siblings with identical compound heterozygous ERCC6 pathogenic variants (c.1526+1G>T; c.2800C>A, p.Pro934Thr) despite marked intrafamilial phenotypic divergence. A combined metabolic stress exposure (galactose, reduced glutamine, and buthionine sulfoximine, (BSO)) which reduced CS cell survival was used to screen for therapeutic leads among twenty-three candidate mitochondrial disease therapeutic compounds. Lead compounds were mechanistically validated at the level of mitochondrial superoxide, total cellular oxidative stress, glutathione, and autophagic flux. Patient fibroblasts exhibited several hallmarks of PMD, including reduced mtDNA content, decreased expression of complex I subunit NDUFB8, elevated expression of TOM20 with paradoxically decreased PGC1α suggestive of impaired mitophagic clearance, and decreased mitochondrial respiratory capacity. Under combined metabolic stress, ATP-levels indicative of survival in CS patient fibroblasts selectively collapsed to ~20% of controls. Five dual-rescue compounds, defined as agents that reproducibly restored ATP-based cell survival in both patient fibroblast lines under stress, were identified, including N-acetylcysteine (NAC), coenzyme Q10 (CoQ10), rapamycin, taurine, and (-)-epicatechin. Mechanistic profiling resolved three functional classes of therapeutic effects in CS cells: (1) upstream mitochondrial reactive oxygen species reduction (NAC, CoQ10); (2) mTORC1 inhibition bypassing defective stress-induced autophagic induction (rapamycin); and (3) extra-mitochondrial improvement in cellular stress resilience ((-)- epicatechin, taurine). ERCC6-based CSB deficiency produced a stress-sensitive and physiologically complex mitochondrial phenotype in patient fibroblasts that was pharmacologically treatable by targeting three mechanistically distinct pathways. Oxidative and broader stress buffering, autophagy modulation via mTORC1 inhibition, and enhanced cellular resilience highlight novel therapeutic opportunities to be advanced to clinical trials in CSB patients.
2026-05-20 | Transcription-coupled nucleotide excision repair protects against genomic instability and cell death induced by the liver toxin methyleugenol.
Methyleugenol (ME) is a hepatotoxic phenylpropene naturally present in various herbs and spices. Following dietary exposure, ME undergoes metabolic activation in the liver, resulting in the formation of DNA adducts and liver damage. Although ME is a suspected human liver carcinogen, it is still unknown which DNA repair pathway removes the ME-induced DNA adducts. Here, we studied the relevance of nucleotide excision repair (NER) using various genetically engineered cell models. Our data show a crucial role for transcription-coupled (TC)-NER rather than global genome (GG)-NER, revealing that ME-induced DNA damage triggers detrimental transcription stress. Mechanistically, ME-derived DNA adducts stall RNA polymerase II (RNAPII), resulting in the chromatin release and cytoplasmic export of its active subunit RPB1, followed by proteasomal degradation to allow for repair and transcription recovery. Blocking of RNAPII by ME-derived DNA lesions promotes CSB immobilization and recruitment of CSA and UVSSA. The triggered canonical TC-NER pathway removes the ME-induced DNA lesions, preserves genome integrity and promotes cell survival. At high DNA adduct levels or in cells with deficient TC-NER, persistent transcription stress provokes genomic instability, induces apoptotic cell death and strongly reduces long-term cell survival. In contrast to that, GG-NER-compromised cells are not sensitized to ME-triggered cytotoxicity. Taken together, the canonical TC-NER pathway is crucial for the repair of DNA adducts induced by ME and likely also structurally related phenylpropenes. These findings are particularly important for Cockayne syndrome patients with defective TC-NER.
Access all drug discovery papers and probability of success in trials forecasts:
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Drug Discovery Landscape
2 orphan drug designations for Cockayne syndrome.
2 orphan drug designations for Cockayne syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
[5,10,15,20-tetrakis(4-carboxyphenyl)-21H,23H-porphine]manganese(III) chloride | small molecules | EMA | 2017-01-12 | — | Institut Pasteur |
D-mannitol and L-proline | small molecules | FDA | 2009-04-20 | — | DNage B.V. |
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