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:
categories:
Small molecules
proteins
2024-02-28 | CSB and SMARCAL1 compete for RPA32 at stalled forks and differentially control the fate of stalled forks in BRCA2-deficient cells
Abstract CSB (Cockayne syndrome group B) and SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent, regulator of chromatin, subfamily A-like 1) are DNA translocases that belong to the SNF2 helicase family. They both are enriched at stalled replication forks. While SMARCAL1 is recruited by RPA32 to stalled forks, little is known about whether RPA32 also regulates CSB’s association with stalled forks. Here, we report that CSB directly interacts with RPA, at least in part via a RPA32C-interacting motif within the N-terminal region of CSB. Modeling of the CSB-RPA32C interaction suggests that CSB binds the RPA32C surface previously shown to be important for binding of UNG2 and SMARCAL1. We show that this interaction is necessary for promoting fork slowing and fork degradation in BRCA2-deficient cells but dispensable for mediating restart of stalled forks. CSB competes with SMARCAL1 for RPA32 at stalled forks and acts non-redundantly with SMARCAL1 to restrain fork progression in response to mild replication stress. In contrast to CSB stimulated restart of stalled forks, SMARCAL1 inhibits restart of stalled forks in BRCA2-deficient cells, likely by suppressing BIR-mediated repair of collapsed forks. Loss of CSB leads to re-sensitization of SMARCAL1-depleted BRCA2-deficient cells to chemodrugs, underscoring a role of CSB in targeted cancer therapy.
2022-02-09 | Cockayne Syndrome B Protein Selectively Resolves and Interact with Intermolecular DNA G-Quadruplex Structures.
Guanine-rich DNA can fold into secondary structures known as G-quadruplexes (G4s). G4s can form from a single DNA strand (intramolecular) or from multiple DNA strands (intermolecular), but studies on their biological functions have been often limited to intramolecular G4s, owing to the low probability of intermolecular G4s to form within genomic DNA. Herein, we report the first example of an endogenous protein, Cockayne Syndrome B (CSB), that can bind selectively with picomolar affinity toward intermolecular G4s formed within rDNA while displaying negligible binding toward intramolecular structures. We observed that CSB can selectively resolve intermolecular over intramolecular G4s, demonstrating that its selectivity toward intermolecular structures is also reflected at the resolvase level. Immunostaining of G4s with the antibody BG4 in CSB-impaired cells (CS1AN) revealed that G4-staining in the nucleolus of these cells can be abrogated by transfection of viable CSB, suggesting that intermolecular G4s can be formed within rDNA and act as binding substrate for CSB. Given that loss of function of CSB elicits premature aging phenotypes, our findings indicate that the interaction between CSB and intermolecular G4s in rDNA could be of relevance to maintain cellular homeostasis.
2022-02-02 | Transcription blockage by DNA damage in nucleotide excision repair-related neurological dysfunctions.
Human genetic syndromes deficient in nucleotide excision repair (NER), such as xeroderma pigmentosum and Cockayne syndrome, may present neurological abnormalities and premature aging symptoms. Unrepaired endogenously generated DNA damage that hampers transcription is a strong candidate that contributes to the development of these severe effects in neuronal tissue. Endogenous lesions include those generated due to byproducts of cellular metabolisms, such as reactive oxygen species. This review presents much of the evidence on the mechanisms related to neurodegenerative processes associated with DNA damage responses. The primary focus is on the effects of the transcription machinery, including the accumulation of DNA•RNA hybrids (R-loops) that, in turn, influence DNA damage and repair metabolism. Moreover, several neuronal tissues present higher expression of long genes, a genomic subset more affected by DNA lesions, which may explain part of the neurological abnormalities in these patients. Also, neuronal tissues have different DNA repair capabilities that might result in different neurological consequences, as observed in patients and NER deficient animal models. The better understanding of how the accumulation of transcription blocking lesions can lead to neurological abnormalities and premature aging-like phenotypes may assist us in finding potential biomarkers and therapeutic targets that might improve the lives of these patients, as well as other neurological disorders in the general population.
2021-02-26 | A CSB-PAF1C axis restores processive transcription elongation after DNA damage repair
Abstract Bulky DNA lesions in transcribed strands block RNA polymerase II (RNAPII) elongation and induce a genome-wide transcriptional arrest. The transcription-coupled repair (TCR) pathway efficiently removes transcription-blocking DNA lesions, but how transcription is restored in the genome following DNA repair remains unresolved. Here, we find that the TCR-specific CSB protein loads the PAF1 complex (PAF1C) onto RNAPII in promoter-proximal regions in response to DNA damage. Although dispensable for TCR-mediated repair, PAF1C is essential for transcription recovery after UV irradiation. We find that PAF1C promotes RNAPII pause release in promoter-proximal regions and subsequently acts as a processivity factor that stimulates transcription elongation throughout genes. Our findings expose the molecular basis for a non-canonical PAF1C-dependent pathway that restores transcription throughout the human genome after genotoxic stress.
2020-12-01 | Cockayne syndrome B protein acts as an ATP-dependent processivity factor that helps RNA polymerase II overcome nucleosome barriers.
While loss-of-function mutations in Cockayne syndrome group B protein (CSB) cause neurological diseases, this unique member of the SWI2/SNF2 family of chromatin remodelers has been broadly implicated in transcription elongation and transcription-coupled DNA damage repair, yet its mechanism remains largely elusive. Here, we use a reconstituted in vitro transcription system with purified polymerase II (Pol II) and Rad26, a yeast ortholog of CSB, to study the role of CSB in transcription elongation through nucleosome barriers. We show that CSB forms a stable complex with Pol II and acts as an ATP-dependent processivity factor that helps Pol II across a nucleosome barrier. This noncanonical mechanism is distinct from the canonical modes of chromatin remodelers that directly engage and remodel nucleosomes or transcription elongation factors that facilitate Pol II nucleosome bypass without hydrolyzing ATP. We propose a model where CSB facilitates gene expression by helping Pol II bypass chromatin obstacles while maintaining their structures.
small molecules
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.
2026-05-04 | Pharmacologic AMPK Activation Extends Lifespan in C. elegans and Improves Aspects of Healthspan in Mice.
Dysregulated energy metabolism is a hallmark of aging. Many interventions that extend lifespan converge on the conserved master regulator of energy metabolism, AMP-activated kinase (AMPK), and direct genetic activation of AMPK extends lifespan in multiple species. Here, we test the ability of a specific and potent pharmacologic AMPK activator, MK-8722, to extend lifespan in C. elegans and improve healthspan in aged mice. Treatment with MK-8722 from adulthood significantly extended lifespan in an AMPK-dependent manner in both wildtype and Cockayne syndrome model csb-1 mutant C. elegans, without impairing motility or reproductive capacity. Mice treated with MK-8722 from 18 until 24 months of age had significantly reduced body fat accumulation, blocked age-associated declines in fasting blood glucose and enhanced circadian rhythmicity in respiratory quotient, suggesting an improved overall metabolic state. Hepatic RNA sequencing revealed a decrease in inflammation-related pathways and an increase in sterol metabolic pathways, which was consistent with significantly increased levels of multiple sterol-derived metabolites, including lithocholic acid, a proposed mediator of the benefits of caloric restriction. Our results support pharmacologic AMPK activation as a promising gerotherapeutic strategy.
2026-03-28 | Integrating Structural, Biochemical, and Cellular Perspectives on the TFIIH Helicases XPB and XPD.
Xeroderma pigmentosum group B (XPB/ERCC3) and group D (XPD/ERCC2) helicases are integral components of the transcription factor IIH (TFIIH) complex, coordinating DNA unwinding during transcription initiation and nucleotide excision repair (NER). XPB functions as an ATP-driven translocase that generates torsional strain to promote promoter melting and DNA opening at lesion sites, whereas XPD acts as a 5' to 3' helicase responsible for lesion verification and extension of the repair bubble. Structural and biochemical studies have clarified how TFIIH subunits regulate these helicases-p52 and p8 modulate XPB's translocation activity, while p44, p62, and MAT1 control XPD's helicase function through conformational and compositional transitions within the complex. Beyond their canonical roles, XPB and XPD participate in diverse cellular pathways, including cell-cycle regulation and oxidative stress response, highlighting their involvement in maintaining genome integrity beyond repair and transcription. Mutations in either helicase lead to xeroderma pigmentosum (XP), trichothiodystrophy (TTD), or combined XP/Cockayne syndrome (XP/CS) phenotypes, emphasizing the essential role of TFIIH integrity for human health. Recent biochemical and pharmacological advances have further revealed the therapeutic relevance of these helicases-XPB as a target of small-molecule inhibitors such as triptolide, Minnelide, and spironolactone, and XPD as a potential modulator of cancer sensitivity to DNA-damaging treatments. Collectively, XPB and XPD exemplify the structural and functional versatility of TFIIH helicases across repair, transcription, and genome maintenance.
gene therapies
2026-07-31 | Pediatric Ocular Abnormalities: A Pictorial Review of Genetic, Metabolic, and Syndromic Associations. Part 1: Abnormalities of the Globe and Lens
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. 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.
2026-01-29 | Familial Occurrence of Cockayne Syndrome: Clinical Insights from Northern India
Background: Cockayne Syndrome (CS) is a rare autosomal recessive neurodegenerative disorder caused by pathogenic variants in ERCC6 (CSB) or ERCC8 (CSA). Key clinical clues include cachexia, microcephaly, characteristic “bird-like” facies, neurodevelopmental regression, sensorineural deficits, and dental anomalies. Radiologically, CS features a characteristic pattern of diffuse hypomyelination, cerebral and cerebellar atrophy, and progressive white matter changes, making MRI a critical adjunct to diagnosis. Case Report and Discussion: We present two affected siblings from a non-consanguineous family with clinical features of CS, including postnatal growth failure, cachectic habitus, bird-like facies, neurodevelopmental regression, and white matter changes with cerebellar atrophy on MRI. Molecular testing identified a homozygous pathogenic ERCC6 variant (c.4063+1G>C) in the affected sibling, confirming the diagnosis. A three-generation pedigree supporting autosomal recessive inheritance is included. Conclusion: This report highlights the phenotype–genotype correlation ansd the importance of neuroimaging and genetic testing for diagnosis, family counseling, and reproductive planning in CS. Early diagnosis enables appropriate supportive care and informed reproductive counseling. Reporting genetically confirmed cases from diverse populations remains important to expand understanding of the disease spectrum and to guide future therapeutic efforts.
2025-12-29 | A Truncating Variant in the ERCC6 Gene With Three Different Phenotypes: Significant Effects of Modifier Genes.
Cockayne syndrome (CS) is a rare, autosomal-recessive, multisystem disorder characterized by microcephaly, failure to thrive, photosensitivity, leukodystrophy, muscle contracture, and intellectual disability. It is caused by deleterious variant in the ERCC6 and ERCC8 genes, which are involved in the transcription-coupled nucleotide excision repair system. According to severity and age of onset, CS is categorized into four types: I, II, III, and cerebrooculofacioskeletal syndrome (COFS). However, some researchers consider COFS to be a distinct disease from CS, while others describe COFS as a severe form of CS. Whole-exome sequencing (WES) and Sanger sequencing were used to identify potential pathogenic causative variant. WES data analysis revealed a nonsense variant (NM_000124: c.3862C>T, p.R1288X) in the ERCC6 gene, which was co-segregated using Sanger sequencing. Although this variant has been reported previously in association with both CS and COFS separately, this study's patient manifested intermediate symptoms. This study's findings expand the clinical spectrum of the variant (NM_000124: c.3862C>T, p.R1288X) and provide more supporting evidence that CS and COFS are phenotypic spectrums rather than different clinical conditions in which genetic and epigenetic factors probably play a pivotal role in the severity of symptoms.
2025-12-04 | Human CSB-deficient iPSCs exhibit impaired DNA damage repair and stress responses following BPDE exposure in an early developmental model
ABSTRACT Maintenance of genome integrity is essential for normal human development, particularly during pre-gastrulation stages when rapid proliferation and intense transcriptional activity increase susceptibility to DNA damage. Environmental genotoxins such as benzo[a]pyrene (BaP), a widespread polycyclic aromatic hydrocarbon, and its reactive metabolite benzo[a]pyrene diol epoxide (BPDE) form bulky DNA adducts that interfere with replication and transcription, thereby posing significant risks to embryonic genome stability. To examine how genetic defects in DNA repair influence these effects, we assessed human induced pluripotent stem cells (iPSCs) carrying pathogenic mutations in ERCC6 (encoding the Cockayne syndrome B, CSB, protein), a key component of transcription-coupled nucleotide excision repair. Pathogenic ERCC6 mutations result in Cockayne syndrome- a severe neurodevelopmental disorder characterized by growth failure, premature aging, and multisystemic degeneration, thus underscoring the essential developmental functions of CSB. Exposure of healthy and CSB-deficient patient derived iPSCs to BPDE revealed impaired proliferation, persistent accumulation of DNA damage and defective checkpoint activation in CSB-deficient lines. Although the levels of key pluripotency-regulating proteins such as OCT4 and NANOG remained unaltered, we observed altered levels of SOX2 and p-SMAD1/5 signaling thus implying that unrepaired DNA damage can perturb developmental-associated signaling pathways and biological processes. Transcriptomic profiling revealed broad suppression of DNA repair and cell-cycle pathways together with activation of p53-, TNFα-, and MAPK/JNK-mediated stress responses in CSB-deficient lines. Failure to induce anti-oxidant defenses, including SOD2 and IDO, further contributed to oxidative imbalance and incomplete apoptotic clearance. These findings demonstrate that CSB function is essential for coupling DNA repair with transcriptional recovery and redox homeostasis in pluripotent cells. Loss of CSB destabilizes the genome stability under genotoxic stress, providing a mechanistic basis for developmental toxicity of environmental polycyclic aromatic hydrocarbons and underscoring the importance of considering genetic susceptibility in developmental toxicology risk assessment.
antibodies
2022-02-01 | Aldehyde-driven transcriptional stress triggers an anorexic DNA damage response.
Endogenous DNA damage can perturb transcription, triggering a multifaceted cellular response that repairs the damage, degrades RNA polymerase II and shuts down global transcription1-4. This response is absent in the human disease Cockayne syndrome, which is caused by loss of the Cockayne syndrome A (CSA) or CSB proteins5-7. However, the source of endogenous DNA damage and how this leads to the prominent degenerative features of this disease remain unknown. Here we find that endogenous formaldehyde impedes transcription, with marked physiological consequences. Mice deficient in formaldehyde clearance (Adh5-/-) and CSB (Csbm/m; Csb is also known as Ercc6) develop cachexia and neurodegeneration, and succumb to kidney failure, features that resemble human Cockayne syndrome. Using single-cell RNA sequencing, we find that formaldehyde-driven transcriptional stress stimulates the expression of the anorexiogenic peptide GDF15 by a subset of kidney proximal tubule cells. Blocking this response with an anti-GDF15 antibody alleviates cachexia in Adh5-/-Csbm/m mice. Therefore, CSB provides protection to the kidney and brain against DNA damage caused by endogenous formaldehyde, while also suppressing an anorexic endocrine signal. The activation of this signal might contribute to the cachexia observed in Cockayne syndrome as well as chemotherapy-induced anorectic weight loss. A plausible evolutionary purpose for such a response is to ensure aversion to genotoxins in food.
proteins
2024-02-28 | CSB and SMARCAL1 compete for RPA32 at stalled forks and differentially control the fate of stalled forks in BRCA2-deficient cells
Abstract CSB (Cockayne syndrome group B) and SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent, regulator of chromatin, subfamily A-like 1) are DNA translocases that belong to the SNF2 helicase family. They both are enriched at stalled replication forks. While SMARCAL1 is recruited by RPA32 to stalled forks, little is known about whether RPA32 also regulates CSB’s association with stalled forks. Here, we report that CSB directly interacts with RPA, at least in part via a RPA32C-interacting motif within the N-terminal region of CSB. Modeling of the CSB-RPA32C interaction suggests that CSB binds the RPA32C surface previously shown to be important for binding of UNG2 and SMARCAL1. We show that this interaction is necessary for promoting fork slowing and fork degradation in BRCA2-deficient cells but dispensable for mediating restart of stalled forks. CSB competes with SMARCAL1 for RPA32 at stalled forks and acts non-redundantly with SMARCAL1 to restrain fork progression in response to mild replication stress. In contrast to CSB stimulated restart of stalled forks, SMARCAL1 inhibits restart of stalled forks in BRCA2-deficient cells, likely by suppressing BIR-mediated repair of collapsed forks. Loss of CSB leads to re-sensitization of SMARCAL1-depleted BRCA2-deficient cells to chemodrugs, underscoring a role of CSB in targeted cancer therapy.
2022-02-09 | Cockayne Syndrome B Protein Selectively Resolves and Interact with Intermolecular DNA G-Quadruplex Structures.
Guanine-rich DNA can fold into secondary structures known as G-quadruplexes (G4s). G4s can form from a single DNA strand (intramolecular) or from multiple DNA strands (intermolecular), but studies on their biological functions have been often limited to intramolecular G4s, owing to the low probability of intermolecular G4s to form within genomic DNA. Herein, we report the first example of an endogenous protein, Cockayne Syndrome B (CSB), that can bind selectively with picomolar affinity toward intermolecular G4s formed within rDNA while displaying negligible binding toward intramolecular structures. We observed that CSB can selectively resolve intermolecular over intramolecular G4s, demonstrating that its selectivity toward intermolecular structures is also reflected at the resolvase level. Immunostaining of G4s with the antibody BG4 in CSB-impaired cells (CS1AN) revealed that G4-staining in the nucleolus of these cells can be abrogated by transfection of viable CSB, suggesting that intermolecular G4s can be formed within rDNA and act as binding substrate for CSB. Given that loss of function of CSB elicits premature aging phenotypes, our findings indicate that the interaction between CSB and intermolecular G4s in rDNA could be of relevance to maintain cellular homeostasis.
2022-02-02 | Transcription blockage by DNA damage in nucleotide excision repair-related neurological dysfunctions.
Human genetic syndromes deficient in nucleotide excision repair (NER), such as xeroderma pigmentosum and Cockayne syndrome, may present neurological abnormalities and premature aging symptoms. Unrepaired endogenously generated DNA damage that hampers transcription is a strong candidate that contributes to the development of these severe effects in neuronal tissue. Endogenous lesions include those generated due to byproducts of cellular metabolisms, such as reactive oxygen species. This review presents much of the evidence on the mechanisms related to neurodegenerative processes associated with DNA damage responses. The primary focus is on the effects of the transcription machinery, including the accumulation of DNA•RNA hybrids (R-loops) that, in turn, influence DNA damage and repair metabolism. Moreover, several neuronal tissues present higher expression of long genes, a genomic subset more affected by DNA lesions, which may explain part of the neurological abnormalities in these patients. Also, neuronal tissues have different DNA repair capabilities that might result in different neurological consequences, as observed in patients and NER deficient animal models. The better understanding of how the accumulation of transcription blocking lesions can lead to neurological abnormalities and premature aging-like phenotypes may assist us in finding potential biomarkers and therapeutic targets that might improve the lives of these patients, as well as other neurological disorders in the general population.
2021-02-26 | A CSB-PAF1C axis restores processive transcription elongation after DNA damage repair
Abstract Bulky DNA lesions in transcribed strands block RNA polymerase II (RNAPII) elongation and induce a genome-wide transcriptional arrest. The transcription-coupled repair (TCR) pathway efficiently removes transcription-blocking DNA lesions, but how transcription is restored in the genome following DNA repair remains unresolved. Here, we find that the TCR-specific CSB protein loads the PAF1 complex (PAF1C) onto RNAPII in promoter-proximal regions in response to DNA damage. Although dispensable for TCR-mediated repair, PAF1C is essential for transcription recovery after UV irradiation. We find that PAF1C promotes RNAPII pause release in promoter-proximal regions and subsequently acts as a processivity factor that stimulates transcription elongation throughout genes. Our findings expose the molecular basis for a non-canonical PAF1C-dependent pathway that restores transcription throughout the human genome after genotoxic stress.
2020-12-01 | Cockayne syndrome B protein acts as an ATP-dependent processivity factor that helps RNA polymerase II overcome nucleosome barriers.
While loss-of-function mutations in Cockayne syndrome group B protein (CSB) cause neurological diseases, this unique member of the SWI2/SNF2 family of chromatin remodelers has been broadly implicated in transcription elongation and transcription-coupled DNA damage repair, yet its mechanism remains largely elusive. Here, we use a reconstituted in vitro transcription system with purified polymerase II (Pol II) and Rad26, a yeast ortholog of CSB, to study the role of CSB in transcription elongation through nucleosome barriers. We show that CSB forms a stable complex with Pol II and acts as an ATP-dependent processivity factor that helps Pol II across a nucleosome barrier. This noncanonical mechanism is distinct from the canonical modes of chromatin remodelers that directly engage and remodel nucleosomes or transcription elongation factors that facilitate Pol II nucleosome bypass without hydrolyzing ATP. We propose a model where CSB facilitates gene expression by helping Pol II bypass chromatin obstacles while maintaining their structures.
small molecules
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.
2026-05-04 | Pharmacologic AMPK Activation Extends Lifespan in C. elegans and Improves Aspects of Healthspan in Mice.
Dysregulated energy metabolism is a hallmark of aging. Many interventions that extend lifespan converge on the conserved master regulator of energy metabolism, AMP-activated kinase (AMPK), and direct genetic activation of AMPK extends lifespan in multiple species. Here, we test the ability of a specific and potent pharmacologic AMPK activator, MK-8722, to extend lifespan in C. elegans and improve healthspan in aged mice. Treatment with MK-8722 from adulthood significantly extended lifespan in an AMPK-dependent manner in both wildtype and Cockayne syndrome model csb-1 mutant C. elegans, without impairing motility or reproductive capacity. Mice treated with MK-8722 from 18 until 24 months of age had significantly reduced body fat accumulation, blocked age-associated declines in fasting blood glucose and enhanced circadian rhythmicity in respiratory quotient, suggesting an improved overall metabolic state. Hepatic RNA sequencing revealed a decrease in inflammation-related pathways and an increase in sterol metabolic pathways, which was consistent with significantly increased levels of multiple sterol-derived metabolites, including lithocholic acid, a proposed mediator of the benefits of caloric restriction. Our results support pharmacologic AMPK activation as a promising gerotherapeutic strategy.
2026-03-28 | Integrating Structural, Biochemical, and Cellular Perspectives on the TFIIH Helicases XPB and XPD.
Xeroderma pigmentosum group B (XPB/ERCC3) and group D (XPD/ERCC2) helicases are integral components of the transcription factor IIH (TFIIH) complex, coordinating DNA unwinding during transcription initiation and nucleotide excision repair (NER). XPB functions as an ATP-driven translocase that generates torsional strain to promote promoter melting and DNA opening at lesion sites, whereas XPD acts as a 5' to 3' helicase responsible for lesion verification and extension of the repair bubble. Structural and biochemical studies have clarified how TFIIH subunits regulate these helicases-p52 and p8 modulate XPB's translocation activity, while p44, p62, and MAT1 control XPD's helicase function through conformational and compositional transitions within the complex. Beyond their canonical roles, XPB and XPD participate in diverse cellular pathways, including cell-cycle regulation and oxidative stress response, highlighting their involvement in maintaining genome integrity beyond repair and transcription. Mutations in either helicase lead to xeroderma pigmentosum (XP), trichothiodystrophy (TTD), or combined XP/Cockayne syndrome (XP/CS) phenotypes, emphasizing the essential role of TFIIH integrity for human health. Recent biochemical and pharmacological advances have further revealed the therapeutic relevance of these helicases-XPB as a target of small-molecule inhibitors such as triptolide, Minnelide, and spironolactone, and XPD as a potential modulator of cancer sensitivity to DNA-damaging treatments. Collectively, XPB and XPD exemplify the structural and functional versatility of TFIIH helicases across repair, transcription, and genome maintenance.
gene therapies
2026-07-31 | Pediatric Ocular Abnormalities: A Pictorial Review of Genetic, Metabolic, and Syndromic Associations. Part 1: Abnormalities of the Globe and Lens
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. 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.
2026-01-29 | Familial Occurrence of Cockayne Syndrome: Clinical Insights from Northern India
Background: Cockayne Syndrome (CS) is a rare autosomal recessive neurodegenerative disorder caused by pathogenic variants in ERCC6 (CSB) or ERCC8 (CSA). Key clinical clues include cachexia, microcephaly, characteristic “bird-like” facies, neurodevelopmental regression, sensorineural deficits, and dental anomalies. Radiologically, CS features a characteristic pattern of diffuse hypomyelination, cerebral and cerebellar atrophy, and progressive white matter changes, making MRI a critical adjunct to diagnosis. Case Report and Discussion: We present two affected siblings from a non-consanguineous family with clinical features of CS, including postnatal growth failure, cachectic habitus, bird-like facies, neurodevelopmental regression, and white matter changes with cerebellar atrophy on MRI. Molecular testing identified a homozygous pathogenic ERCC6 variant (c.4063+1G>C) in the affected sibling, confirming the diagnosis. A three-generation pedigree supporting autosomal recessive inheritance is included. Conclusion: This report highlights the phenotype–genotype correlation ansd the importance of neuroimaging and genetic testing for diagnosis, family counseling, and reproductive planning in CS. Early diagnosis enables appropriate supportive care and informed reproductive counseling. Reporting genetically confirmed cases from diverse populations remains important to expand understanding of the disease spectrum and to guide future therapeutic efforts.
2025-12-29 | A Truncating Variant in the ERCC6 Gene With Three Different Phenotypes: Significant Effects of Modifier Genes.
Cockayne syndrome (CS) is a rare, autosomal-recessive, multisystem disorder characterized by microcephaly, failure to thrive, photosensitivity, leukodystrophy, muscle contracture, and intellectual disability. It is caused by deleterious variant in the ERCC6 and ERCC8 genes, which are involved in the transcription-coupled nucleotide excision repair system. According to severity and age of onset, CS is categorized into four types: I, II, III, and cerebrooculofacioskeletal syndrome (COFS). However, some researchers consider COFS to be a distinct disease from CS, while others describe COFS as a severe form of CS. Whole-exome sequencing (WES) and Sanger sequencing were used to identify potential pathogenic causative variant. WES data analysis revealed a nonsense variant (NM_000124: c.3862C>T, p.R1288X) in the ERCC6 gene, which was co-segregated using Sanger sequencing. Although this variant has been reported previously in association with both CS and COFS separately, this study's patient manifested intermediate symptoms. This study's findings expand the clinical spectrum of the variant (NM_000124: c.3862C>T, p.R1288X) and provide more supporting evidence that CS and COFS are phenotypic spectrums rather than different clinical conditions in which genetic and epigenetic factors probably play a pivotal role in the severity of symptoms.
2025-12-04 | Human CSB-deficient iPSCs exhibit impaired DNA damage repair and stress responses following BPDE exposure in an early developmental model
ABSTRACT Maintenance of genome integrity is essential for normal human development, particularly during pre-gastrulation stages when rapid proliferation and intense transcriptional activity increase susceptibility to DNA damage. Environmental genotoxins such as benzo[a]pyrene (BaP), a widespread polycyclic aromatic hydrocarbon, and its reactive metabolite benzo[a]pyrene diol epoxide (BPDE) form bulky DNA adducts that interfere with replication and transcription, thereby posing significant risks to embryonic genome stability. To examine how genetic defects in DNA repair influence these effects, we assessed human induced pluripotent stem cells (iPSCs) carrying pathogenic mutations in ERCC6 (encoding the Cockayne syndrome B, CSB, protein), a key component of transcription-coupled nucleotide excision repair. Pathogenic ERCC6 mutations result in Cockayne syndrome- a severe neurodevelopmental disorder characterized by growth failure, premature aging, and multisystemic degeneration, thus underscoring the essential developmental functions of CSB. Exposure of healthy and CSB-deficient patient derived iPSCs to BPDE revealed impaired proliferation, persistent accumulation of DNA damage and defective checkpoint activation in CSB-deficient lines. Although the levels of key pluripotency-regulating proteins such as OCT4 and NANOG remained unaltered, we observed altered levels of SOX2 and p-SMAD1/5 signaling thus implying that unrepaired DNA damage can perturb developmental-associated signaling pathways and biological processes. Transcriptomic profiling revealed broad suppression of DNA repair and cell-cycle pathways together with activation of p53-, TNFα-, and MAPK/JNK-mediated stress responses in CSB-deficient lines. Failure to induce anti-oxidant defenses, including SOD2 and IDO, further contributed to oxidative imbalance and incomplete apoptotic clearance. These findings demonstrate that CSB function is essential for coupling DNA repair with transcriptional recovery and redox homeostasis in pluripotent cells. Loss of CSB destabilizes the genome stability under genotoxic stress, providing a mechanistic basis for developmental toxicity of environmental polycyclic aromatic hydrocarbons and underscoring the importance of considering genetic susceptibility in developmental toxicology risk assessment.
antibodies
2022-02-01 | Aldehyde-driven transcriptional stress triggers an anorexic DNA damage response.
Endogenous DNA damage can perturb transcription, triggering a multifaceted cellular response that repairs the damage, degrades RNA polymerase II and shuts down global transcription1-4. This response is absent in the human disease Cockayne syndrome, which is caused by loss of the Cockayne syndrome A (CSA) or CSB proteins5-7. However, the source of endogenous DNA damage and how this leads to the prominent degenerative features of this disease remain unknown. Here we find that endogenous formaldehyde impedes transcription, with marked physiological consequences. Mice deficient in formaldehyde clearance (Adh5-/-) and CSB (Csbm/m; Csb is also known as Ercc6) develop cachexia and neurodegeneration, and succumb to kidney failure, features that resemble human Cockayne syndrome. Using single-cell RNA sequencing, we find that formaldehyde-driven transcriptional stress stimulates the expression of the anorexiogenic peptide GDF15 by a subset of kidney proximal tubule cells. Blocking this response with an anti-GDF15 antibody alleviates cachexia in Adh5-/-Csbm/m mice. Therefore, CSB provides protection to the kidney and brain against DNA damage caused by endogenous formaldehyde, while also suppressing an anorexic endocrine signal. The activation of this signal might contribute to the cachexia observed in Cockayne syndrome as well as chemotherapy-induced anorectic weight loss. A plausible evolutionary purpose for such a response is to ensure aversion to genotoxins in food.
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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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