RARE DISEASE
Aicardi-Goutières syndrome
Aicardi-Goutières syndrome
Aicardi-Goutières syndrome
Synonyms: Encephalopathy with basal ganglia calcification, Encephalopathy with intracranial calcification and chronic lymphocytosis of cerebrospinal fluid
Synonyms: Encephalopathy with basal ganglia calcification, Encephalopathy with intracranial calcification and chronic lymphocytosis of cerebrospinal fluid
Synonyms: Encephalopathy with basal ganglia calcification, Encephalopathy with intracranial calcification and chronic lymphocytosis of cerebrospinal fluid
Drug discovery
3
drugs
With orphan designations
Overview
Aicardi-Goutières syndrome (AGS) is a rare genetic interferonopathy characterized by early-onset encephalopathy, basal ganglia calcification, leukodystrophy, and systemic inflammation. It arises from mutations in genes (TREX1, RNASEH2A/B/C, SAMHD1, ADAR1, IFIH1) involved in nucleic acid metabolism, leading to chronic type I interferon activation. Clinical features include developmental regression, spasticity, microcephaly, chilblains, and sterile fevers mimicking congenital infection [1][7][12].
Therapies
JAK inhibitors (baricitinib, ruxolitinib): Reduce interferon signaling, improve irritability/skin lesions [8][13].
RNA-targeted therapy: Antisense oligonucleotides against IFN-α receptor in preclinical trials [3].
Supportive care: Spasticity management, feeding support, and monitoring systemic complications (pulmonary, hepatic) [11][16].
Categories: rare genetic diseases, rare neurological diseases, rare systemic and rheumatological diseases, rare systemic or rheumatologic diseases of childhood
Research Papers
329 drug discovery papers about Aicardi-Goutières syndrome, with 4 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
329 drug discovery papers about Aicardi-Goutières syndrome, with 4 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-07-28 | Targeting Novel DNase Therapeutic to Intracellular cGAS—STING Pathway for DNA Clearance in TREX1-Deficient Aicardi-Goutières Syndrome 2329186
Abstract Introduction Aicardi—Goutières syndrome (AGS) is an early onset progressive encephalopathy induced by biallelic pathogenic variants in genes responsible for degrading or sensing cytoplasmic nucleic acids. AGS exhibits phenotypic overlap with Systemic lupus erythematosus (SLE) in that both are type 1 interferonopathies, but AGS may additionally induce microcephaly, seizures, developmental delays, and significant mortality in infants. Approximately 30% of AGS cases are due to TREX1 deficiency. To investigate the role of extracellular nucleic acid signaling in the pathogenesis of AGS we examined the effects of a long acting DNase biologic with dual DNAse1/DNAse1L3 activity (called 1687) on the survival and cytokine profiles of Trex1-/- mice. Methods We treated Trex1-/- mice weekly with vehicle or subcutaneous injections of 1687 at 1 mg/Kg, and monitored survival for 250 days. A smaller cohort underwent mechanistic analysis of immune biomarkers (cytokines, autoantibodies) and molecular pathways. Results Vehicle treated Trex1-/- mice succumbed to disease as early as five weeks of age with a median survival of 98.5 days, while mortality in the Trex1-/- treated mice began around 10 weeks of age and did not reach a median survival within the 250-day window. At 250 days approximately 80% of the vehicle treated Trex1-/- mice had expired, compared with approximately 45% of the 1687 treated Trex1-/- mice. Treated mice displayed reductions in extracellular inflammatory cytokines along with reduced anti-dsDNA and MYH6 auto-antibodies. However, no differences in cytokines induced by the intracellular cGAS—STING pathway were observed in treated and untreated animals. Conclusion Our findings document a pathogenic role for extracellular DNA signaling in AGS, a disease whose accepted pathogenic mechanism is defective intracellular nucleic acid signaling. Our results further suggest that extracellular DNA clearance may offer a therapeutic benefit to AGS patients. Funding Source Colton Center for Autoimmunity Topic Categories Therapeutic Approaches to Autoimmunity (THER)
2025-11-01 | STING activation, DNA clearance, and autoimmune disease: investigating pathogenic mechanisms with DNase dysfunction and novel therapeutics in SLE and AGS models 4696
Abstract Description Background In healthy individuals, DNase1, DNase1L3, and TREX1 enzymes clear excess chromatin and DNA. Mutations or autoantibodies against these enzymes impair DNA clearance, causing DNA accumulation at inflammatory sites. Systemic lupus erythematosus (SLE) is a leading cause of death among young U.S. women and shares features with type I interferonopathies like Aicardi-Goutières syndrome (AGS), a rare autoimmune disorder marked by neuroinflammation where 30% of cases are due to TREX1 deficiency. Objective: This project investigates the therapeutic potential of a novel DNase biologic in autoimmune diseases resulting from TREX1 deficiency, aiming to advance our understanding of the enzyme’s role in disorders like SLE and AGS. Methods We engineered a long-acting DNase biologic and assessed efficacy in an AGS mouse model (Trex1 knockout, TKO). Survival in treated mice was monitored over 250 days; a smaller cohort underwent mechanistic analysis of immune biomarkers (cytokines, autoantibodies) and molecular pathways. Results DNase biologic-treated mice showed improved survival over controls. Treatment also reduced biomarkers such as dsDNA/MYH6 autoantibodies, CXCL10, and IFN-γ. Untreated TKO mice experienced significant weight loss and myocarditis, which were alleviated in treated mice. Conclusions The DNase biologic showed on-target activity that partially rescued a TKO-driven AGS model, suggesting biologic restoration of DNA clearance may offer a novel approach to treatment. Funding Sources Supported by Colton Center of Autoimmunity Topic Categories Therapeutic Approaches to Autoimmunity (THER)
2023-07-25 | Construction and characterization of ribonuclease H2 C subunit-knockout NIH3T3 cells.
Mammalian ribonuclease (RNase) H2 is a trimer consisting of catalytic A and accessory B and C subunits. RNase H2 is involved in the removal of misincorporated ribonucleotides from genomic DNA. In humans, mutations in RNase H2 gene cause a severe neuroinflammatory disorder, Aicardi-Goutières syndrome (AGS). Here, we constructed RNase H2 C subunit (RH2C)-knockout mouse fibroblast NIH3T3 cells. Compared with the wild-type NIH3T3 cells, the knockout cells exhibited a decreased single ribonucleotide-hydrolyzing activity and an increased accumulation of ribonucleotides in genomic DNA. Transient expression of wild-type RH2C in the knockout cells increased this activity and decreased this ribonucleotide accumulation. Same events were observed when RH2C variants with an AGS-causing mutation, R69W or K145I, were expressed. These results corresponded with our previous results on the RNase H2 A subunit (RH2A)-knockout NIH3T3 cells and the expression of wild-type RH2A or RH2A variants with an AGS-causing mutation, N213I and R293H, in the RH2A-knockout cells.
2023-05-05 | The phenotype of the most common human ADAR1p150 Zα mutation P193A in mice is partially penetrant.
ADAR1 -mediated A-to-I RNA editing is a self-/non-self-discrimination mechanism for cellular double-stranded RNAs. ADAR mutations are one cause of Aicardi-Goutières Syndrome, an inherited paediatric encephalopathy, classed as a "Type I interferonopathy." The most common ADAR1 mutation is a proline 193 alanine (p.P193A) mutation, mapping to the ADAR1p150 isoform-specific Zα domain. Here, we report the development of an independent murine P195A knock-in mouse, homologous to human P193A. The Adar1P195A/P195A mice are largely normal and the mutation is well tolerated. When the P195A mutation is compounded with an Adar1 null allele (Adar1P195A/- ), approximately half the animals are runted with a shortened lifespan while the remaining Adar1P195A/- animals are normal, contrasting with previous reports. The phenotype of the Adar1P195A/- animals is both associated with the parental genotype and partly non-genetic/environmental. Complementation with an editing-deficient ADAR1 (Adar1P195A/E861A ), or the loss of MDA5, rescues phenotypes in the Adar1P195A/- mice.
2023-05-04 | Recombinant Klotho attenuates IFNγ receptor signaling and SAMHD1 expression through blocking NF-κB translocation in glomerular mesangial cells
Interferon gamma (IFNγ) is a cytokine implicated in the pathogenesis of autoimmune diseases. SAM and HD domain-containing protein 1 (SAMHD1) is an IFNγ-inducible protein that modulates cellular dNTP levels. Mutations in the human SAMHD1 gene cause Aicardi-Goutières (AG) syndrome, an autoimmune disease sharing similar clinical features with systemic lupus erythematosus (SLE). Klotho is an anti-inflammatory protein which suppresses aging through multiple mechanisms. Implication of Klotho in autoimmune response is identified in rheumatologic diseases such as SLE. Little information exists regarding the effect of Klotho in lupus nephritis, one of the prevalent symptoms of SLE. The present study verified the effect of IFNγ on SAMHD1 and Klotho expression in MES-13 glomerular mesangial cells, a special cell type in glomerulus that is critically involved in lupus nephritis. IFNγ upregulated SAMHD1 expression in MES-13 cells through the Janus kinase-signal transducer and activator of transcription 1 (JAK-STAT1) and the nuclear factor kappa B (NFκB) signaling pathways. IFNγ decreased Klotho protein expression in MES-13 cells. Treatment of MES-13 cells with recombinant Klotho protein inhibited SAMHD1 expression by blocking IFNγ-induced NFκB nuclear translocation, but showed no effect on JAK-STAT1 signaling. Collectively, our findings support the protective role of Klotho in attenuating lupus nephritis through the inhibition of IFNγ-induced SAMHD1 expression and IFNγ downstream signaling in MES-13 cells.
small molecules
2026-09-09 | Targeting type I interferonopathy in Aicardi–Goutières Syndrome: Pediatric case series and systematic review
Introduction: Aicardi–Goutières Syndrome (AGS) is a prototypic type I interferonopathy characterized by chronic interferon signalling, early-onset neuroinflammation, and frequently irreversible neurological damage. Janus kinase inhibitors (JAKi) have emerged as a targeted therapeutic option, [for full text, please go to the a.m. URL]
2026-09-03 | Neonatal Aicardi-Goutières syndrome presenting with macrophage activation syndrome-like hyperinflammation and severe congenital glaucoma: a case report.
Neonatal-onset Aicardi-Goutières syndrome (AGS) is a rare monogenic type I interferonopathy that may mimic congenital infection and can present with severe multisystem inflammation. The distinction between primary hemophagocytic lymphohistiocytosis (HLH) and AGS-associated macrophage activation syndrome (MAS)-like hyperinflammation can be challenging in neonates. We report a term neonate presenting with cholestatic jaundice, a generalized blueberry muffin-like ecchymotic-purpuric rash, cytopenias, hyperferritinemia, hepatosplenomegaly, intracranial calcifications, and severe bilateral congenital glaucoma. Extensive infectious evaluation was negative. The patient fulfilled five of eight HLH-2004 criteria, consistent with a severe MAS-like hyperinflammatory phenotype. Dexamethasone and intravenous immunoglobulin had been initiated at the referring center for presumed virus-associated HLH but were not continued after transfer to our unit. With persistent disease activity, negative microbiological studies, and neuroimaging strongly suggestive of a type I interferonopathy, ruxolitinib was initiated on day of life (DOL) 34 before molecular confirmation. Exome sequencing subsequently identified homozygous pathogenic variants in RNASEH2B and CYP1B1, supporting AGS type 2 and primary congenital glaucoma (glaucoma 3 A), respectively. Serial laboratory data showed sustained improvement after initiation of JAK1/2 inhibition, although the observational nature of a single case and other immunomodulatory exposures limit causal attribution. This case illustrates the clinical overlap between neonatal AGS and MAS-like hyperinflammation, underscores the potential role of early mechanism-based therapy in selected critically ill neonates with suspected interferonopathy, and emphasizes the importance of comprehensive genomic evaluation when severe ocular disease accompanies AGS. The identified CYP1B1 variant provides a strong molecular explanation for the patient's congenital glaucoma.
2026-09-03 | Inositol hexakisphosphate is a Cofactor and Modulator of ADAR1 RNA Editing Activity.
Adenosine-to-inosine (A-to-I) RNA editing by ADAR1 is a key post-transcriptional modification, and mutations in ADAR1 lead to Aicardi-Goutières syndrome (AGS), an autoimmune disorder. Despite its biological and clinical relevance, the regulation of ADAR1 activity remains incompletely understood. Using a combination of biochemical approaches, inositol-pentakisphosphate 2-kinase (IPPK)-knockout cells, molecular dynamics simulations, and a cell-permeable inositol hexakisphosphate (IP6) prodrug (Pro-IP6), we demonstrate that IP6 depletion drastically reduces global RNA editing, while supplementation with Pro-IP6 restores and even enhances editing levels. Furthermore, we identify the C6-phosphate of IP6 as a critical determinant of ADAR1 catalytic efficiency, functioning within a hydrogen-bonding network that indirectly coordinates a Zn²⁺-ion. Finally, we show that the AGS-associated ADAR1 mutation N907S impairs RNA editing activity, most likely by altering the hydrogen-bond interaction network linking IP6 to the ADAR1 catalytic center. Together, these findings identify IP6 as an essential cofactor and regulator of ADAR1 activity and highlight cofactor availability and interaction networks as strategies for therapeutically modulating RNA editing.
2026-08-06 | Immune response to DNA and RNA: structural insights, molecular mechanisms, and therapeutic targeting.
The recognition of mislocalized DNA and RNA by cGAS-STING, RIG-I/MDA5, the OAS-RNase L axis, and endosomal TLR3/7/8 has emerged as a unifying paradigm linking cancer, autoinflammation, and antiviral immunity. Counterbalancing these sensors is a structurally heterogeneous nuclease repertoire whose distinct substrate specificities, subcellular compartments and pH optima constrain ligand availability in space and time. Disruption of this equilibrium drives disease through two mirror-image mechanisms. In cancer, DNASE1 is inactivated by tumor-derived G-actin, DNASE1L3 is transcriptionally silenced in hepatocellular, colorectal and lung adenocarcinomas, and DNASE2 is upregulated in immunologically "cold" tumors, together permitting neutrophil-extracellular-trap-mediated exclusion of cytotoxic T cells and suppression of cytosolic DNA sensing. In autoimmunity, biallelic loss of DNASE1L3, TREX1, RNase H2, ADAR1 or RNase T2 produces the interferonopathies of systemic lupus and Aicardi-Goutières syndrome. Diagnostically, nuclease-specific cleavage signatures have matured into cell-free DNA fragmentomics validated across 13 cancer types in a 3,021-patient cohort; therapeutically, the field now spans engineered actin-resistant DNASE1/DNASE1L3 biologics, selective TREX1 and ADAR1 inhibitors entering first-in-human evaluation, STING-activating nanomedicines, RNase Fc-fusions such as RSLV-132 in phase 2a lupus, and JAK1/2 inhibition as standard of care in Aicardi-Goutières syndrome. We synthesize this evidence as a two-fate problem: whether an endogenous nucleic acid accumulates at these sensors to drive autoinflammation or is cleared by nucleases before detection is set by the balance between sensor engagement and clearance capacity. The therapeutic corollary acts on the ligand rather than the enzyme, restoring ligand availability where disease is malignant and restoring clearance where disease is self-directed.
2026-08-04 | A molecular glue induces aberrant STING oligomerization and inhibits autoinflammatory diseases.
Dysregulated activation of the stimulator of interferon genes (STING) pathway underlies various inflammatory and autoimmune pathologies. Since STING oligomerization is fundamental to its biological function, targeted modulation of this polymerization process presents a promising therapeutic approach. However, achieving precise control over STING polymerization has remained a significant challenge. In this study, we report that benzofuran derivatives serve as molecular glues to potently inhibit STING activity by inducing its aberrant oligomerization. Structural analyses demonstrated that these compounds function as glues, promoting an unconventional "head-to-head" STING dimerization configuration that differs markedly from the linear polymers formed during canonical pathway activation. These compounds exhibit potent inhibitory activity against different STING isoforms activated by 2',3'-cGAMP, dsDNA, gain-of-function SAVI-associated STING mutant, and herpes simplex virus type 1 (HSV-1) infection. DDO-6513 downregulates the expression of type I interferons (IFN-I), IFN-stimulated genes (ISGs) and pro-inflammatory cytokines in clinical samples isolated from patients with STING-associated autoimmune disorders, including Aicardi-Goutières syndrome (AGS), systemic lupus erythematosus (SLE), and dermatomyositis (DM). In vivo, DDO-7432 displays desirable drug-like properties, and exerts remarkable anti-inflammatory efficacy in murine myositis disease models. Our findings demonstrate that modulating protein oligomerization via molecular glues can effectively disrupt signal transduction, providing novel insights into therapeutic strategies for oligomerization-dependent targets.
oligonucleotides
2026-04-09 | A-to-I RNA Editing: From Molecular Mechanism to Therapeutic Application in Biomedicine
Adenosine-to-inosine (A-to-I) RNA editing is a fundamental post-transcriptional modification catalyzed by the Adenosine Deaminase Acting on RNA (ADAR) enzyme family. This process involves the hydrolytic deamination of adenosine to inosine within double-stranded RNA (dsRNA) structures, which is subsequently interpreted as guanosine by cellular machinery. This effectively recodes genetic information at the transcript level, expanding proteomic diversity. The ADAR family in mammals includes the catalytically active ADAR1 and ADAR2, and the inactive ADAR3. ADAR1, which is ubiquitously expressed, plays a critical role in innate immunity by editing endogenous dsRNAs (often formed by Alu elements) to mark them as 'self' and prevent activation of antiviral pathways by sensors like MDA5. ADAR2 is predominantly expressed in the nervous system and is vital for editing key neuronal transcripts, such as glutamate receptors, to fine-tune synaptic function. Dysregulation of A-to-I editing is implicated in numerous human diseases. In cancer, altered editing of oncogenes like AZIN1 and tumor suppressors can drive tumor progression and therapy resistance. In autoimmune disorders like Aicardi-Goutieres syndrome, ADAR1 mutations lead to chronic interferon responses. This deep biological understanding has spurred the development of therapeutic platforms that use guide RNAs or chemically modified oligonucleotides to recruit endogenous ADARs to correct pathogenic point mutations, offering a transient and tunable alternative to permanent DNA editing. Source: https://www.rnabiosci.com/posts/atoi-rna-editing-from-molecular-mechanism-to-therapeutic-application-in-biomedicine
2025-01-04 | A Wonderful Journey: The Diverse Roles of Adenosine Deaminase Action on RNA 1 (ADAR1) in Central Nervous System Diseases.
Adenosine deaminase action on RNA 1 (ADAR1) can convert the adenosine in double-stranded RNA (dsRNA) molecules into inosine in a process known as A-to-I RNA editing. ADAR1 regulates gene expression output by interacting with RNA and other proteins; plays important roles in development, including growth; and is linked to innate immunity, tumors, and central nervous system (CNS) diseases. In recent years, the role of ADAR1 in tumors has been widely discussed, but its role in CNS diseases has not been reviewed. It is worth noting that recent studies have shown ADAR1 has great potential in the treatment of neurodegenerative diseases, but the mechanisms are still unclear. Therefore, it is necessary to elaborate on the role of ADAR1 in CNS diseases. Here, we focus on the effects and mechanisms of ADAR1 on CNS diseases such as Aicardi-AicardiGoutières syndrome, Alzheimer's disease, Parkinson's disease, glioblastoma, epilepsy, amyotrophic lateral sclerosis, and autism. We also evaluate the impact of ADAR1-based treatment strategies on these diseases, with a particular focus on the development and treatment strategies of new technologies such as microRNAs, nanotechnology, gene editing, and stem cell therapy. We hope to provide new directions and insights for the future development of ADAR1 gene editing technology in brain science and the treatment of CNS diseases.
2024-05-01 | Target specificity in the ADAR editing landscape explains the unique immunoregulatory function of the interferon-inducible isoform ADAR1-p150
Abstract The adenosine deaminase acting on RNA (ADAR) family includes three enzymes, ADAR1-p150, ADAR1-p110, and ADAR2 that bind endogenous and pathogen-derived double-stranded RNA (dsRNA) and convert adenosine (A) to inosine (I). This process called A-to-I editing disrupts dsRNA structures and counteracts activation of innate immune sensors MDA-5 and PKR, preventing autoimmune disorders like Aicardi-Goutieres-Syndrome. We and others have shown that the interferon-inducible ADAR1-p150, but not the other ADARs, protects cells and organisms from aberrant innate immune activation by self-derived dsRNA, even though A-to-I editing is performed by all three ADARs. We hypothesized that ADAR1-p150 edits specific transcripts that cannot be edited by the other enzymes. Here we present a novel approach to quantify RNA editing in transcriptomic data. Our tool TSniffer detected more than 40,000 regions of A-to-I editing distributed over the entire human transcriptome, affecting 30% of protein-coding transcripts and 10% of long non-coding RNAs. Differential editing frequencies in cell lines with knock-outs for the different ADARs revealed transcripts exclusively edited by ADAR1-p150. In contrast, editing by ADAR1-p110 and ADAR2 was cooperative and more redundant. Our analyses fill gaps of knowledge about the A-to-I editing landscape, highlight the dominant immunoregulatory function of ADAR1-p150, and provide new insights in the role of aberrant A-to-I editing in disease development.
2024-02-16 | Interferon-α receptor antisense oligonucleotides reduce neuroinflammation and neuropathology in a mouse model of cerebral interferonopathy.
Chronic and elevated levels of the antiviral cytokine IFN-α in the brain are neurotoxic. This is best observed in patients with genetic cerebral interferonopathies such as Aicardi-Goutières syndrome. Cerebral interferonopathies typically manifest in early childhood and lead to debilitating disease and premature death. There is no cure for these diseases with existing treatments largely aimed at managing symptoms. Thus, an effective therapeutic strategy is urgently needed. Here, we investigated the effect of antisense oligonucleotides targeting the murine IFN-α receptor (Ifnar1 ASOs) in a transgenic mouse model of cerebral interferonopathy. Intracerebroventricular injection of Ifnar1 ASOs into transgenic mice with brain-targeted chronic IFN-α production resulted in a blunted cerebral interferon signature, reduced neuroinflammation, restoration of blood-brain barrier integrity, absence of tissue destruction, and lessened neuronal damage. Remarkably, Ifnar1 ASO treatment was also effective when given after the onset of neuropathological changes, as it reversed such disease-related features. We conclude that ASOs targeting the IFN-α receptor halt and reverse progression of IFN-α-mediated neuroinflammation and neurotoxicity, opening what we believe to be a new and promising approach for the treatment of patients with cerebral interferonopathies.
2023-11-01 | Long 3'UTRs predispose neurons to inflammation by promoting immunostimulatory double-stranded RNA formation.
Loss of RNA homeostasis underlies numerous neurodegenerative and neuroinflammatory diseases. However, the molecular mechanisms that trigger neuroinflammation are poorly understood. Viral double-stranded RNA (dsRNA) triggers innate immune responses when sensed by host pattern recognition receptors (PRRs) present in all cell types. Here, we report that human neurons intrinsically carry exceptionally high levels of immunostimulatory dsRNAs and identify long 3'UTRs as giving rise to neuronal dsRNA structures. We found that the neuron-enriched ELAVL family of genes (ELAVL2, ELAVL3, and ELAVL4) can increase (i) 3'UTR length, (ii) dsRNA load, and (iii) activation of dsRNA-sensing PRRs such as MDA5, PKR, and TLR3. In wild-type neurons, neuronal dsRNAs signaled through PRRs to induce tonic production of the antiviral type I interferon. Depleting ELAVL2 in WT neurons led to global shortening of 3'UTR length, reduced immunostimulatory dsRNA levels, and rendered WT neurons susceptible to herpes simplex virus and Zika virus infection. Neurons deficient in ADAR1, a dsRNA-editing enzyme mutated in the neuroinflammatory disorder Aicardi-Goutières syndrome, exhibited intolerably high levels of dsRNA that triggered PRR-mediated toxic inflammation and neuronal death. Depleting ELAVL2 in ADAR1 knockout neurons led to prolonged neuron survival by reducing immunostimulatory dsRNA levels. In summary, neurons are specialized cells where PRRs constantly sense "self" dsRNAs to preemptively induce protective antiviral immunity, but maintaining RNA homeostasis is paramount to prevent pathological neuroinflammation.
gene therapies
2026-03-17 | Aicardi-Goutières Syndrome: Insights from a Middle Eastern Case Series.
Aicardi-Goutières syndrome (AGS) is a rare, genetically-determined spectrum of neurodegenerative disorders that remains poorly understood. Owing to the paucity of data from Middle-Eastern population, we aimed to delineate the clinical, radiological, and genetic features of AGS in an under-represented Middle-Eastern cohort. A retrospective case-series review was performed of all genetically-confirmed AGS cases managed at a tertiary pediatric hospital in Qatar between November 2016 and December 2024. Demographic, clinical, radiologic, and genetic data were extracted; white-matter (WM) disease severity and imaging course were graded, and associations with genotype were explored. Fifteen individuals (73.3% male; 80% consanguinity) were identified. Symptom onset occurred in the infantile age in 86.7%, with developmental delay or regression (100%), intellectual impairment (76.9%), and impaired motor function (69.2%) predominating. Two siblings with SAMHD1-homozygous variant were neurologically normal but had chronic arthritis. Genetic variants were identified in RNASEH2B (26.7%), RNASEH2A and TREX1 (each 20%), followed by ADAR1 and SAMHD1 (each 13.3%), and RNASEH2C (6.7%); 80% of variants were homozygous. Radiological assessment was suggestive of the disease in 40% of the cases. Initial neuroimaging revealed focal WM disease in 76.9%, calcifications in 53.8%, hypomyelination in 38.5%, and basal-ganglia involvement in 30.8%. WM disease was absent (13.3%), mild (40.0%), moderate (40%), or severe (6.7%); follow-up imaging showed stable (10%), regressive (30%), progressive (40%), or progressive-then-regressive (20%) course of imaging findings, independent of the genotype and clinical course. Genotype correlated significantly with WM disease severity at presentation (p < 0.05), but not with longitudinal imaging trajectory. Intrafamilial radiological discordance was observed in half of the family clusters. This AGS series from a Middle-Eastern population broadens the phenotypic spectrum, highlighting high homozygosity and RNASEH2 predominance in a highly consanguineous population, a significant genotype-WM disease severity link, and radiologic variability independent of genotype or clinical course. Awareness of these patterns may inform population-based testing and management strategies. AGS ＝Aicardi-Goutières syndrome; VUS ＝ variant of uncertain significance.
2026-02-18 | Heterozygous ADAR mutant mice exhibit RNA sensing-dependent neuroinflammation and phenotypes associated with Aicardi-Goutières syndrome.
The ADAR G1007R mutation is frequently found in type six Aicardi-Goutières syndrome (AGS), a severe inflammatory encephalopathy in pediatric patients, and is distinct in having a phenotype in heterozygotes. To define the mechanisms underlying this disease, we developed an ADAR G1007 heterozygous mouse model that recapitulates the genetic and inflammatory features of individuals with ADAR G1007R AGS. These mice exhibited increased astrocytosis and microgliosis and interferon-stimulated gene (ISG) expression within deep brain areas. Additionally, brain inflammation was reversed by deletion of MDA5, which blocks cellular RNA sensing. Analysis of embryonic RNAs show the G1007R mutation also interrupts the splicing donor site in RNA transcripts, thereby altering ADAR1 RNA splicing and depleting the ADAR1 protein. Collectively, this study reports an animal model for AGS manifesting a heterozygous phenotype, reveals molecular defects associated with the ADAR G1007R mutation, and demonstrates that MDA5-dependent RNA sensing contributes to neuroinflammation.
2025-09-08 | Microgliosis and aberrant interferon response in Adar Mavs brain are rescued by PKR removal.
Mutations in the human ADAR gene, encoding adenosine deaminase acting on RNA 1 (ADAR1), cause Aicardi-Goutières syndrome 6, which is a severe auto-inflammatory encephalopathy with aberrant interferon (IFN) induction. AdarΔ2-13 null mutant mouse embryos lacking ADAR1 protein die with high levels of IFN-stimulated gene (ISG) transcripts. In Adar Mavs double mutants also lacking the Mitochondrial antiviral signalling (MAVS) adaptor, the aberrant IFN induction is prevented. Live pups are born and survive for 2 weeks, allowing ADAR1 function to be investigated. We have shown that early death of Adar Mavs mutants is rescued by the deletion of the Eif2ak2 gene encoding the antiviral dsRNA sensor protein kinase R (PKR). Here, we focused on characterizing the brain defects in Adar Mavs mutants and their dependencies on PKR. Mouse brains were collected on postnatal Days 8 and 14, then analysed by mass spectrometry, immunohistochemistry and RT-qPCR. The proteomic analyses showed upregulation of ISG-encoded proteins in the Adar Mavs double mutant, and the morphological analyses confirmed aberrant microgliosis in the brains. Both are prevented in Adar Mavs Eif2ak2 triple mutants, indicating the key role of aberrant PKR activation; PKR expression is also increased by IFN signalling. Altered expression levels of transcripts encoding differentially expressed proteins and of ADAR-edited transcripts were confirmed by RT-qPCR. Analysis of the expression levels of transcripts in the brains of mutants expressing a catalytically inactive ADAR E861A protein revealed that the levels of some but not all altered transcripts are restored. A further group of proteins, downregulated in Adar Mavs double mutants, are not rescued by removal of PKR and might result from effects of loss of the widespread ADAR1 RNA editing known to occur in brain transcripts. This group includes several motor proteins, some of which have been reported to be encoded by ADAR-edited transcripts. In this study, we show that Adar Mavs double mutants exhibit an aberrant IFN response in the brain, probably attributable to reactive microglia and astrocytes. Microgliosis, which is rescued in the triple mutant, is mostly dependent on aberrant PKR activation and is partly dependent on RNA editing.
2025-08-01 | Dual pathology of parvovirus B19 infection and Aicardi-Goutières syndrome complicating non-immune hydrops fetalis.
Non-immune hydrops fetalis (NIHF) is a multifactorial condition characterised by abnormal fluid accumulation in fetal compartments. We report a complex case of NIHF in a primigravida in her 30s with dual pathology involving fetal parvovirus B19 infection and Aicardi-Goutières syndrome (AGS) due to a TREX1 gene mutation. The fetus exhibited severe anaemia, hydrops fetalis, ventriculomegaly and brain calcifications. Whole exome sequencing confirmed AGS as the genetic aetiology, while PCR on amniotic fluid identified parvovirus B19 as a coexisting infection. Although AGS alone has varied phenotype and prognosis but due to coexisting severe anaemia, the neonate succumbed postnatally. This report highlights the importance of integrating genetic and infectious workups in atypical NIHF cases.
2025-04-21 | Aicardi-Goutières Syndrome Associated ADAR G1007R mutation dominantly induces neuroinflammation in mouse brain
Abstract The ADAR G 1007 R mutation is one of the most frequent mutations found in type six Aicardi-Goutières Syndrome (AGS), a severe inflammatory encephalopathy in pediatric patients. We report here a mouse model bearing an human equivalent ADAR G 1007 R mutation, and the heterozygous mice recapitulated some pathologic features of ADAR G 1007 R AGS patients, including early-onset brain inflammation in heterozygous individuals and interferon-stimulated gene (ISG) expression within deep brain areas. Furthermore, we demonstrated that brain inflammation could be reversed by deletion of the cellular RNA receptor MDA5, which blocks the cellular RNA sensing signaling pathway. This model provides a unique tool for studying the molecular mechanisms underlying the heterozygous ADAR WT/G 1007 R mutation in AGS brain pathogenesis. It may also be a valuable platform for developing personalized therapies for patients with this specific mutation.
other
2026-01-27 | Author response: Microglia replacement by ER-Hoxb8 conditionally immortalized macrophages provides insight into Aicardi–Goutières syndrome neuropathology
A microglia replacement approach demonstrates that brain macrophages with patient mutations from Aicardi–Goutières syndrome, a genetic, brain predominant interferonopathy, are sufficient to drive interferon responses.
2026-01-27 | Basic Microglial Functions and How They Go Awry in Neurodegenerative Disease.
Microglia-the parenchymal tissue-resident macrophages of the brain and spinal cord-are essential to support brain health by integrating environmental cues and performing immune functions and reparative processes. Yet across neurodegenerative diseases, these long-lived cells become increasingly unable to meet the demands of their homeostatic roles. In this review, we trace the arc of microglial function from competence to dysfunction, examining how their roles, for example, in synaptic pruning, phagocytosis, and interferon signaling, can shift from protective to pathogenic. Using Alzheimer's disease, inherited microgliopathies, and Aicardi-Goutières syndrome as case studies, we highlight the ways in which microglia fail-through metabolic exhaustion, lysosomal overload, inflammatory gain of function, or failure to respond. We consider how genetic and environmental factors converge to drive this "microglial incompetence," and discuss emerging strategies to reset or replace dysfunctional microglia. Understanding when and how microglia go awry may unlock new paths for treating a wide spectrum of neurodegenerative diseases.
2026-01-10 | Microglia replacement by ER-Hoxb8 conditionally immortalized macrophages provides insight into Aicardi–Goutières syndrome neuropathology
Microglia, the brain’s resident macrophages, can be reconstituted by surrogate cells – a process termed ‘microglia replacement’. To expand the microglia replacement toolkit, we here introduce estrogen-regulated (ER) homeobox B8 (Hoxb8) conditionally immortalized macrophages, a cell model for generation of immune cells from murine bone marrow, as a versatile model for microglia replacement. We find that ER-Hoxb8 macrophages are highly comparable to primary bone marrow-derived macrophages in vitro, and, when transplanted into a microglia-free brain, engraft the parenchyma and differentiate into microglia-like cells. Furthermore, ER-Hoxb8 progenitors are readily transducible by virus and easily stored as stable, genetically manipulated cell lines. As a demonstration of this system’s power for studying the effects of disease mutations on microglia in vivo, we created stable, Adar1-mutated ER-Hoxb8 lines using CRISPR-Cas9 to study the intrinsic contribution of macrophages to Aicardi–Goutières syndrome (AGS), an inherited interferonopathy that primarily affects the brain and immune system. We find that Adar1 knockout elicited interferon secretion and impaired macrophage production in vitro, while preventing brain macrophage engraftment in vivo – phenotypes that can be rescued with concurrent mutation of Ifih1 (MDA5) in vitro, but not in vivo. Lastly, we extended these findings by generating ER-Hoxb8 progenitors from mice harboring a patient-specific Adar1 mutation (D1113H). We demonstrated the ability of microglia-specific D1113H mutation to drive interferon production in vivo, suggesting microglia drive AGS neuropathology. In sum, we introduce the ER-Hoxb8 approach to model microglia replacement and use it to clarify macrophage contributions to AGS.
2025-07-03 | Deep Brain Stimulation in a Child with Aicardi‐Goutières Syndrome‐7 ( AGS7 ): A Case Report and Literature Review
Aicardi-Goutières syndrome (AGS) is a clinically and genetically heterogeneous group of disorders with neurological and systemic findings.Some individuals present with early-onset encephalopathy, whereas others exhibit normal development followed by regression of milestones.Other signs include intellectual disability, irritability, spasticity, dystonia, acquired microcephaly, sterile pyrexia, chilblains, and hepatosplenomegaly. 1 AGS is caused by homozygous variants in ADAR (OMIM: 146920), RNASEH2A (OMIM: 606034), RNASEH2B (OMIM: 610326), RNASEH2C (OMIM: 610330), SAMHD1 (OMIM; 606754), TREX1 (OMIM: 606609), RNU7-1 (OMIM: 617876), or LSM11 (OMIM: 617910) genes and heterozygous pathogenic variants in TREX1, ADAR, or IFIH1 (OMIM: 606951) genes.1,2 Here we describe a child with AGS7 who had progressive dystonia and was managed with deep brain stimulation (DBS).An 8.5-year-old girl born to nonconsanguineous parents was referred for the management of progressive dystonia and regression of milestones.The mother reported fetal hypokinesia.The baby was born full term by vacuum-assisted delivery with a birth weight of 3150 g, and the neonatal transition was uneventful.Her motor milestones were mildly delayed from 6 months of age.She had a gradual regression of milestones from 18 months of age.Assessment at 21 months of age revealed normocephaly, spasticity of all four limbs, brisk deep tendon reflexes, bilateral ankle clonus, and dystonia of bilateral lower limbs.Brain magnetic resonance imaging (MRI) at 2 years of age (Fig. S1A-F )
2025-06-30 | eLife Assessment: Microglia replacement by ER-Hoxb8 conditionally immortalized macrophages provides insight into Aicardi-Goutières Syndrome neuropathology
Microglia, the brain’s resident macrophages, can be reconstituted by surrogate cells - a process termed “microglia replacement.” To expand the microglia replacement toolkit, we here introduce estrogen-regulated (ER) homeobox B8 (Hoxb8) conditionally immortalized macrophages, a cell model for generation of immune cells from murine bone marrow, as a versatile model for microglia replacement. We find that ER-Hoxb8 macrophages are highly comparable to primary bone marrow-derived (BMD) macrophages in vitro, and, when transplanted into a microglia-free brain, engraft the parenchyma and differentiate into microglia-like cells. Furthermore, ER-Hoxb8 progenitors are readily transducible by virus and easily stored as stable, genetically manipulated cell lines. As a demonstration of this system’s power for studying the effects of disease mutations on microglia in vivo, we created stable, Adar1-mutated ER-Hoxb8 lines using CRISPR-Cas9 to study the intrinsic contribution of macrophages to Aicardi-Goutières Syndrome (AGS), an inherited interferonopathy that primarily affects the brain and immune system. We find that Adar1 knockout elicited interferon secretion and impaired macrophage production in vitro, while preventing brain macrophage engraftment in vivo - phenotypes that can be rescued with concurrent mutation of Ifih1 (MDA5) in vitro, but not in vivo. Lastly, we extended these findings by generating ER-Hoxb8 progenitors from mice harboring a patient-specific Adar1 mutation (D1113H). We demonstrated the ability of microglia-specific D1113H mutation to drive interferon production in vivo, suggesting microglia drive AGS neuropathology. In sum, we introduce the ER-Hoxb8 approach to model microglia replacement and use it to clarify macrophage contributions to AGS.
proteins
2026-07-28 | Targeting Novel DNase Therapeutic to Intracellular cGAS—STING Pathway for DNA Clearance in TREX1-Deficient Aicardi-Goutières Syndrome 2329186
Abstract Introduction Aicardi—Goutières syndrome (AGS) is an early onset progressive encephalopathy induced by biallelic pathogenic variants in genes responsible for degrading or sensing cytoplasmic nucleic acids. AGS exhibits phenotypic overlap with Systemic lupus erythematosus (SLE) in that both are type 1 interferonopathies, but AGS may additionally induce microcephaly, seizures, developmental delays, and significant mortality in infants. Approximately 30% of AGS cases are due to TREX1 deficiency. To investigate the role of extracellular nucleic acid signaling in the pathogenesis of AGS we examined the effects of a long acting DNase biologic with dual DNAse1/DNAse1L3 activity (called 1687) on the survival and cytokine profiles of Trex1-/- mice. Methods We treated Trex1-/- mice weekly with vehicle or subcutaneous injections of 1687 at 1 mg/Kg, and monitored survival for 250 days. A smaller cohort underwent mechanistic analysis of immune biomarkers (cytokines, autoantibodies) and molecular pathways. Results Vehicle treated Trex1-/- mice succumbed to disease as early as five weeks of age with a median survival of 98.5 days, while mortality in the Trex1-/- treated mice began around 10 weeks of age and did not reach a median survival within the 250-day window. At 250 days approximately 80% of the vehicle treated Trex1-/- mice had expired, compared with approximately 45% of the 1687 treated Trex1-/- mice. Treated mice displayed reductions in extracellular inflammatory cytokines along with reduced anti-dsDNA and MYH6 auto-antibodies. However, no differences in cytokines induced by the intracellular cGAS—STING pathway were observed in treated and untreated animals. Conclusion Our findings document a pathogenic role for extracellular DNA signaling in AGS, a disease whose accepted pathogenic mechanism is defective intracellular nucleic acid signaling. Our results further suggest that extracellular DNA clearance may offer a therapeutic benefit to AGS patients. Funding Source Colton Center for Autoimmunity Topic Categories Therapeutic Approaches to Autoimmunity (THER)
2025-11-01 | STING activation, DNA clearance, and autoimmune disease: investigating pathogenic mechanisms with DNase dysfunction and novel therapeutics in SLE and AGS models 4696
Abstract Description Background In healthy individuals, DNase1, DNase1L3, and TREX1 enzymes clear excess chromatin and DNA. Mutations or autoantibodies against these enzymes impair DNA clearance, causing DNA accumulation at inflammatory sites. Systemic lupus erythematosus (SLE) is a leading cause of death among young U.S. women and shares features with type I interferonopathies like Aicardi-Goutières syndrome (AGS), a rare autoimmune disorder marked by neuroinflammation where 30% of cases are due to TREX1 deficiency. Objective: This project investigates the therapeutic potential of a novel DNase biologic in autoimmune diseases resulting from TREX1 deficiency, aiming to advance our understanding of the enzyme’s role in disorders like SLE and AGS. Methods We engineered a long-acting DNase biologic and assessed efficacy in an AGS mouse model (Trex1 knockout, TKO). Survival in treated mice was monitored over 250 days; a smaller cohort underwent mechanistic analysis of immune biomarkers (cytokines, autoantibodies) and molecular pathways. Results DNase biologic-treated mice showed improved survival over controls. Treatment also reduced biomarkers such as dsDNA/MYH6 autoantibodies, CXCL10, and IFN-γ. Untreated TKO mice experienced significant weight loss and myocarditis, which were alleviated in treated mice. Conclusions The DNase biologic showed on-target activity that partially rescued a TKO-driven AGS model, suggesting biologic restoration of DNA clearance may offer a novel approach to treatment. Funding Sources Supported by Colton Center of Autoimmunity Topic Categories Therapeutic Approaches to Autoimmunity (THER)
2023-07-25 | Construction and characterization of ribonuclease H2 C subunit-knockout NIH3T3 cells.
Mammalian ribonuclease (RNase) H2 is a trimer consisting of catalytic A and accessory B and C subunits. RNase H2 is involved in the removal of misincorporated ribonucleotides from genomic DNA. In humans, mutations in RNase H2 gene cause a severe neuroinflammatory disorder, Aicardi-Goutières syndrome (AGS). Here, we constructed RNase H2 C subunit (RH2C)-knockout mouse fibroblast NIH3T3 cells. Compared with the wild-type NIH3T3 cells, the knockout cells exhibited a decreased single ribonucleotide-hydrolyzing activity and an increased accumulation of ribonucleotides in genomic DNA. Transient expression of wild-type RH2C in the knockout cells increased this activity and decreased this ribonucleotide accumulation. Same events were observed when RH2C variants with an AGS-causing mutation, R69W or K145I, were expressed. These results corresponded with our previous results on the RNase H2 A subunit (RH2A)-knockout NIH3T3 cells and the expression of wild-type RH2A or RH2A variants with an AGS-causing mutation, N213I and R293H, in the RH2A-knockout cells.
2023-05-05 | The phenotype of the most common human ADAR1p150 Zα mutation P193A in mice is partially penetrant.
ADAR1 -mediated A-to-I RNA editing is a self-/non-self-discrimination mechanism for cellular double-stranded RNAs. ADAR mutations are one cause of Aicardi-Goutières Syndrome, an inherited paediatric encephalopathy, classed as a "Type I interferonopathy." The most common ADAR1 mutation is a proline 193 alanine (p.P193A) mutation, mapping to the ADAR1p150 isoform-specific Zα domain. Here, we report the development of an independent murine P195A knock-in mouse, homologous to human P193A. The Adar1P195A/P195A mice are largely normal and the mutation is well tolerated. When the P195A mutation is compounded with an Adar1 null allele (Adar1P195A/- ), approximately half the animals are runted with a shortened lifespan while the remaining Adar1P195A/- animals are normal, contrasting with previous reports. The phenotype of the Adar1P195A/- animals is both associated with the parental genotype and partly non-genetic/environmental. Complementation with an editing-deficient ADAR1 (Adar1P195A/E861A ), or the loss of MDA5, rescues phenotypes in the Adar1P195A/- mice.
2023-05-04 | Recombinant Klotho attenuates IFNγ receptor signaling and SAMHD1 expression through blocking NF-κB translocation in glomerular mesangial cells
Interferon gamma (IFNγ) is a cytokine implicated in the pathogenesis of autoimmune diseases. SAM and HD domain-containing protein 1 (SAMHD1) is an IFNγ-inducible protein that modulates cellular dNTP levels. Mutations in the human SAMHD1 gene cause Aicardi-Goutières (AG) syndrome, an autoimmune disease sharing similar clinical features with systemic lupus erythematosus (SLE). Klotho is an anti-inflammatory protein which suppresses aging through multiple mechanisms. Implication of Klotho in autoimmune response is identified in rheumatologic diseases such as SLE. Little information exists regarding the effect of Klotho in lupus nephritis, one of the prevalent symptoms of SLE. The present study verified the effect of IFNγ on SAMHD1 and Klotho expression in MES-13 glomerular mesangial cells, a special cell type in glomerulus that is critically involved in lupus nephritis. IFNγ upregulated SAMHD1 expression in MES-13 cells through the Janus kinase-signal transducer and activator of transcription 1 (JAK-STAT1) and the nuclear factor kappa B (NFκB) signaling pathways. IFNγ decreased Klotho protein expression in MES-13 cells. Treatment of MES-13 cells with recombinant Klotho protein inhibited SAMHD1 expression by blocking IFNγ-induced NFκB nuclear translocation, but showed no effect on JAK-STAT1 signaling. Collectively, our findings support the protective role of Klotho in attenuating lupus nephritis through the inhibition of IFNγ-induced SAMHD1 expression and IFNγ downstream signaling in MES-13 cells.
small molecules
2026-09-09 | Targeting type I interferonopathy in Aicardi–Goutières Syndrome: Pediatric case series and systematic review
Introduction: Aicardi–Goutières Syndrome (AGS) is a prototypic type I interferonopathy characterized by chronic interferon signalling, early-onset neuroinflammation, and frequently irreversible neurological damage. Janus kinase inhibitors (JAKi) have emerged as a targeted therapeutic option, [for full text, please go to the a.m. URL]
2026-09-03 | Neonatal Aicardi-Goutières syndrome presenting with macrophage activation syndrome-like hyperinflammation and severe congenital glaucoma: a case report.
Neonatal-onset Aicardi-Goutières syndrome (AGS) is a rare monogenic type I interferonopathy that may mimic congenital infection and can present with severe multisystem inflammation. The distinction between primary hemophagocytic lymphohistiocytosis (HLH) and AGS-associated macrophage activation syndrome (MAS)-like hyperinflammation can be challenging in neonates. We report a term neonate presenting with cholestatic jaundice, a generalized blueberry muffin-like ecchymotic-purpuric rash, cytopenias, hyperferritinemia, hepatosplenomegaly, intracranial calcifications, and severe bilateral congenital glaucoma. Extensive infectious evaluation was negative. The patient fulfilled five of eight HLH-2004 criteria, consistent with a severe MAS-like hyperinflammatory phenotype. Dexamethasone and intravenous immunoglobulin had been initiated at the referring center for presumed virus-associated HLH but were not continued after transfer to our unit. With persistent disease activity, negative microbiological studies, and neuroimaging strongly suggestive of a type I interferonopathy, ruxolitinib was initiated on day of life (DOL) 34 before molecular confirmation. Exome sequencing subsequently identified homozygous pathogenic variants in RNASEH2B and CYP1B1, supporting AGS type 2 and primary congenital glaucoma (glaucoma 3 A), respectively. Serial laboratory data showed sustained improvement after initiation of JAK1/2 inhibition, although the observational nature of a single case and other immunomodulatory exposures limit causal attribution. This case illustrates the clinical overlap between neonatal AGS and MAS-like hyperinflammation, underscores the potential role of early mechanism-based therapy in selected critically ill neonates with suspected interferonopathy, and emphasizes the importance of comprehensive genomic evaluation when severe ocular disease accompanies AGS. The identified CYP1B1 variant provides a strong molecular explanation for the patient's congenital glaucoma.
2026-09-03 | Inositol hexakisphosphate is a Cofactor and Modulator of ADAR1 RNA Editing Activity.
Adenosine-to-inosine (A-to-I) RNA editing by ADAR1 is a key post-transcriptional modification, and mutations in ADAR1 lead to Aicardi-Goutières syndrome (AGS), an autoimmune disorder. Despite its biological and clinical relevance, the regulation of ADAR1 activity remains incompletely understood. Using a combination of biochemical approaches, inositol-pentakisphosphate 2-kinase (IPPK)-knockout cells, molecular dynamics simulations, and a cell-permeable inositol hexakisphosphate (IP6) prodrug (Pro-IP6), we demonstrate that IP6 depletion drastically reduces global RNA editing, while supplementation with Pro-IP6 restores and even enhances editing levels. Furthermore, we identify the C6-phosphate of IP6 as a critical determinant of ADAR1 catalytic efficiency, functioning within a hydrogen-bonding network that indirectly coordinates a Zn²⁺-ion. Finally, we show that the AGS-associated ADAR1 mutation N907S impairs RNA editing activity, most likely by altering the hydrogen-bond interaction network linking IP6 to the ADAR1 catalytic center. Together, these findings identify IP6 as an essential cofactor and regulator of ADAR1 activity and highlight cofactor availability and interaction networks as strategies for therapeutically modulating RNA editing.
2026-08-06 | Immune response to DNA and RNA: structural insights, molecular mechanisms, and therapeutic targeting.
The recognition of mislocalized DNA and RNA by cGAS-STING, RIG-I/MDA5, the OAS-RNase L axis, and endosomal TLR3/7/8 has emerged as a unifying paradigm linking cancer, autoinflammation, and antiviral immunity. Counterbalancing these sensors is a structurally heterogeneous nuclease repertoire whose distinct substrate specificities, subcellular compartments and pH optima constrain ligand availability in space and time. Disruption of this equilibrium drives disease through two mirror-image mechanisms. In cancer, DNASE1 is inactivated by tumor-derived G-actin, DNASE1L3 is transcriptionally silenced in hepatocellular, colorectal and lung adenocarcinomas, and DNASE2 is upregulated in immunologically "cold" tumors, together permitting neutrophil-extracellular-trap-mediated exclusion of cytotoxic T cells and suppression of cytosolic DNA sensing. In autoimmunity, biallelic loss of DNASE1L3, TREX1, RNase H2, ADAR1 or RNase T2 produces the interferonopathies of systemic lupus and Aicardi-Goutières syndrome. Diagnostically, nuclease-specific cleavage signatures have matured into cell-free DNA fragmentomics validated across 13 cancer types in a 3,021-patient cohort; therapeutically, the field now spans engineered actin-resistant DNASE1/DNASE1L3 biologics, selective TREX1 and ADAR1 inhibitors entering first-in-human evaluation, STING-activating nanomedicines, RNase Fc-fusions such as RSLV-132 in phase 2a lupus, and JAK1/2 inhibition as standard of care in Aicardi-Goutières syndrome. We synthesize this evidence as a two-fate problem: whether an endogenous nucleic acid accumulates at these sensors to drive autoinflammation or is cleared by nucleases before detection is set by the balance between sensor engagement and clearance capacity. The therapeutic corollary acts on the ligand rather than the enzyme, restoring ligand availability where disease is malignant and restoring clearance where disease is self-directed.
2026-08-04 | A molecular glue induces aberrant STING oligomerization and inhibits autoinflammatory diseases.
Dysregulated activation of the stimulator of interferon genes (STING) pathway underlies various inflammatory and autoimmune pathologies. Since STING oligomerization is fundamental to its biological function, targeted modulation of this polymerization process presents a promising therapeutic approach. However, achieving precise control over STING polymerization has remained a significant challenge. In this study, we report that benzofuran derivatives serve as molecular glues to potently inhibit STING activity by inducing its aberrant oligomerization. Structural analyses demonstrated that these compounds function as glues, promoting an unconventional "head-to-head" STING dimerization configuration that differs markedly from the linear polymers formed during canonical pathway activation. These compounds exhibit potent inhibitory activity against different STING isoforms activated by 2',3'-cGAMP, dsDNA, gain-of-function SAVI-associated STING mutant, and herpes simplex virus type 1 (HSV-1) infection. DDO-6513 downregulates the expression of type I interferons (IFN-I), IFN-stimulated genes (ISGs) and pro-inflammatory cytokines in clinical samples isolated from patients with STING-associated autoimmune disorders, including Aicardi-Goutières syndrome (AGS), systemic lupus erythematosus (SLE), and dermatomyositis (DM). In vivo, DDO-7432 displays desirable drug-like properties, and exerts remarkable anti-inflammatory efficacy in murine myositis disease models. Our findings demonstrate that modulating protein oligomerization via molecular glues can effectively disrupt signal transduction, providing novel insights into therapeutic strategies for oligomerization-dependent targets.
oligonucleotides
2026-04-09 | A-to-I RNA Editing: From Molecular Mechanism to Therapeutic Application in Biomedicine
Adenosine-to-inosine (A-to-I) RNA editing is a fundamental post-transcriptional modification catalyzed by the Adenosine Deaminase Acting on RNA (ADAR) enzyme family. This process involves the hydrolytic deamination of adenosine to inosine within double-stranded RNA (dsRNA) structures, which is subsequently interpreted as guanosine by cellular machinery. This effectively recodes genetic information at the transcript level, expanding proteomic diversity. The ADAR family in mammals includes the catalytically active ADAR1 and ADAR2, and the inactive ADAR3. ADAR1, which is ubiquitously expressed, plays a critical role in innate immunity by editing endogenous dsRNAs (often formed by Alu elements) to mark them as 'self' and prevent activation of antiviral pathways by sensors like MDA5. ADAR2 is predominantly expressed in the nervous system and is vital for editing key neuronal transcripts, such as glutamate receptors, to fine-tune synaptic function. Dysregulation of A-to-I editing is implicated in numerous human diseases. In cancer, altered editing of oncogenes like AZIN1 and tumor suppressors can drive tumor progression and therapy resistance. In autoimmune disorders like Aicardi-Goutieres syndrome, ADAR1 mutations lead to chronic interferon responses. This deep biological understanding has spurred the development of therapeutic platforms that use guide RNAs or chemically modified oligonucleotides to recruit endogenous ADARs to correct pathogenic point mutations, offering a transient and tunable alternative to permanent DNA editing. Source: https://www.rnabiosci.com/posts/atoi-rna-editing-from-molecular-mechanism-to-therapeutic-application-in-biomedicine
2025-01-04 | A Wonderful Journey: The Diverse Roles of Adenosine Deaminase Action on RNA 1 (ADAR1) in Central Nervous System Diseases.
Adenosine deaminase action on RNA 1 (ADAR1) can convert the adenosine in double-stranded RNA (dsRNA) molecules into inosine in a process known as A-to-I RNA editing. ADAR1 regulates gene expression output by interacting with RNA and other proteins; plays important roles in development, including growth; and is linked to innate immunity, tumors, and central nervous system (CNS) diseases. In recent years, the role of ADAR1 in tumors has been widely discussed, but its role in CNS diseases has not been reviewed. It is worth noting that recent studies have shown ADAR1 has great potential in the treatment of neurodegenerative diseases, but the mechanisms are still unclear. Therefore, it is necessary to elaborate on the role of ADAR1 in CNS diseases. Here, we focus on the effects and mechanisms of ADAR1 on CNS diseases such as Aicardi-AicardiGoutières syndrome, Alzheimer's disease, Parkinson's disease, glioblastoma, epilepsy, amyotrophic lateral sclerosis, and autism. We also evaluate the impact of ADAR1-based treatment strategies on these diseases, with a particular focus on the development and treatment strategies of new technologies such as microRNAs, nanotechnology, gene editing, and stem cell therapy. We hope to provide new directions and insights for the future development of ADAR1 gene editing technology in brain science and the treatment of CNS diseases.
2024-05-01 | Target specificity in the ADAR editing landscape explains the unique immunoregulatory function of the interferon-inducible isoform ADAR1-p150
Abstract The adenosine deaminase acting on RNA (ADAR) family includes three enzymes, ADAR1-p150, ADAR1-p110, and ADAR2 that bind endogenous and pathogen-derived double-stranded RNA (dsRNA) and convert adenosine (A) to inosine (I). This process called A-to-I editing disrupts dsRNA structures and counteracts activation of innate immune sensors MDA-5 and PKR, preventing autoimmune disorders like Aicardi-Goutieres-Syndrome. We and others have shown that the interferon-inducible ADAR1-p150, but not the other ADARs, protects cells and organisms from aberrant innate immune activation by self-derived dsRNA, even though A-to-I editing is performed by all three ADARs. We hypothesized that ADAR1-p150 edits specific transcripts that cannot be edited by the other enzymes. Here we present a novel approach to quantify RNA editing in transcriptomic data. Our tool TSniffer detected more than 40,000 regions of A-to-I editing distributed over the entire human transcriptome, affecting 30% of protein-coding transcripts and 10% of long non-coding RNAs. Differential editing frequencies in cell lines with knock-outs for the different ADARs revealed transcripts exclusively edited by ADAR1-p150. In contrast, editing by ADAR1-p110 and ADAR2 was cooperative and more redundant. Our analyses fill gaps of knowledge about the A-to-I editing landscape, highlight the dominant immunoregulatory function of ADAR1-p150, and provide new insights in the role of aberrant A-to-I editing in disease development.
2024-02-16 | Interferon-α receptor antisense oligonucleotides reduce neuroinflammation and neuropathology in a mouse model of cerebral interferonopathy.
Chronic and elevated levels of the antiviral cytokine IFN-α in the brain are neurotoxic. This is best observed in patients with genetic cerebral interferonopathies such as Aicardi-Goutières syndrome. Cerebral interferonopathies typically manifest in early childhood and lead to debilitating disease and premature death. There is no cure for these diseases with existing treatments largely aimed at managing symptoms. Thus, an effective therapeutic strategy is urgently needed. Here, we investigated the effect of antisense oligonucleotides targeting the murine IFN-α receptor (Ifnar1 ASOs) in a transgenic mouse model of cerebral interferonopathy. Intracerebroventricular injection of Ifnar1 ASOs into transgenic mice with brain-targeted chronic IFN-α production resulted in a blunted cerebral interferon signature, reduced neuroinflammation, restoration of blood-brain barrier integrity, absence of tissue destruction, and lessened neuronal damage. Remarkably, Ifnar1 ASO treatment was also effective when given after the onset of neuropathological changes, as it reversed such disease-related features. We conclude that ASOs targeting the IFN-α receptor halt and reverse progression of IFN-α-mediated neuroinflammation and neurotoxicity, opening what we believe to be a new and promising approach for the treatment of patients with cerebral interferonopathies.
2023-11-01 | Long 3'UTRs predispose neurons to inflammation by promoting immunostimulatory double-stranded RNA formation.
Loss of RNA homeostasis underlies numerous neurodegenerative and neuroinflammatory diseases. However, the molecular mechanisms that trigger neuroinflammation are poorly understood. Viral double-stranded RNA (dsRNA) triggers innate immune responses when sensed by host pattern recognition receptors (PRRs) present in all cell types. Here, we report that human neurons intrinsically carry exceptionally high levels of immunostimulatory dsRNAs and identify long 3'UTRs as giving rise to neuronal dsRNA structures. We found that the neuron-enriched ELAVL family of genes (ELAVL2, ELAVL3, and ELAVL4) can increase (i) 3'UTR length, (ii) dsRNA load, and (iii) activation of dsRNA-sensing PRRs such as MDA5, PKR, and TLR3. In wild-type neurons, neuronal dsRNAs signaled through PRRs to induce tonic production of the antiviral type I interferon. Depleting ELAVL2 in WT neurons led to global shortening of 3'UTR length, reduced immunostimulatory dsRNA levels, and rendered WT neurons susceptible to herpes simplex virus and Zika virus infection. Neurons deficient in ADAR1, a dsRNA-editing enzyme mutated in the neuroinflammatory disorder Aicardi-Goutières syndrome, exhibited intolerably high levels of dsRNA that triggered PRR-mediated toxic inflammation and neuronal death. Depleting ELAVL2 in ADAR1 knockout neurons led to prolonged neuron survival by reducing immunostimulatory dsRNA levels. In summary, neurons are specialized cells where PRRs constantly sense "self" dsRNAs to preemptively induce protective antiviral immunity, but maintaining RNA homeostasis is paramount to prevent pathological neuroinflammation.
gene therapies
2026-03-17 | Aicardi-Goutières Syndrome: Insights from a Middle Eastern Case Series.
Aicardi-Goutières syndrome (AGS) is a rare, genetically-determined spectrum of neurodegenerative disorders that remains poorly understood. Owing to the paucity of data from Middle-Eastern population, we aimed to delineate the clinical, radiological, and genetic features of AGS in an under-represented Middle-Eastern cohort. A retrospective case-series review was performed of all genetically-confirmed AGS cases managed at a tertiary pediatric hospital in Qatar between November 2016 and December 2024. Demographic, clinical, radiologic, and genetic data were extracted; white-matter (WM) disease severity and imaging course were graded, and associations with genotype were explored. Fifteen individuals (73.3% male; 80% consanguinity) were identified. Symptom onset occurred in the infantile age in 86.7%, with developmental delay or regression (100%), intellectual impairment (76.9%), and impaired motor function (69.2%) predominating. Two siblings with SAMHD1-homozygous variant were neurologically normal but had chronic arthritis. Genetic variants were identified in RNASEH2B (26.7%), RNASEH2A and TREX1 (each 20%), followed by ADAR1 and SAMHD1 (each 13.3%), and RNASEH2C (6.7%); 80% of variants were homozygous. Radiological assessment was suggestive of the disease in 40% of the cases. Initial neuroimaging revealed focal WM disease in 76.9%, calcifications in 53.8%, hypomyelination in 38.5%, and basal-ganglia involvement in 30.8%. WM disease was absent (13.3%), mild (40.0%), moderate (40%), or severe (6.7%); follow-up imaging showed stable (10%), regressive (30%), progressive (40%), or progressive-then-regressive (20%) course of imaging findings, independent of the genotype and clinical course. Genotype correlated significantly with WM disease severity at presentation (p < 0.05), but not with longitudinal imaging trajectory. Intrafamilial radiological discordance was observed in half of the family clusters. This AGS series from a Middle-Eastern population broadens the phenotypic spectrum, highlighting high homozygosity and RNASEH2 predominance in a highly consanguineous population, a significant genotype-WM disease severity link, and radiologic variability independent of genotype or clinical course. Awareness of these patterns may inform population-based testing and management strategies. AGS ＝Aicardi-Goutières syndrome; VUS ＝ variant of uncertain significance.
2026-02-18 | Heterozygous ADAR mutant mice exhibit RNA sensing-dependent neuroinflammation and phenotypes associated with Aicardi-Goutières syndrome.
The ADAR G1007R mutation is frequently found in type six Aicardi-Goutières syndrome (AGS), a severe inflammatory encephalopathy in pediatric patients, and is distinct in having a phenotype in heterozygotes. To define the mechanisms underlying this disease, we developed an ADAR G1007 heterozygous mouse model that recapitulates the genetic and inflammatory features of individuals with ADAR G1007R AGS. These mice exhibited increased astrocytosis and microgliosis and interferon-stimulated gene (ISG) expression within deep brain areas. Additionally, brain inflammation was reversed by deletion of MDA5, which blocks cellular RNA sensing. Analysis of embryonic RNAs show the G1007R mutation also interrupts the splicing donor site in RNA transcripts, thereby altering ADAR1 RNA splicing and depleting the ADAR1 protein. Collectively, this study reports an animal model for AGS manifesting a heterozygous phenotype, reveals molecular defects associated with the ADAR G1007R mutation, and demonstrates that MDA5-dependent RNA sensing contributes to neuroinflammation.
2025-09-08 | Microgliosis and aberrant interferon response in Adar Mavs brain are rescued by PKR removal.
Mutations in the human ADAR gene, encoding adenosine deaminase acting on RNA 1 (ADAR1), cause Aicardi-Goutières syndrome 6, which is a severe auto-inflammatory encephalopathy with aberrant interferon (IFN) induction. AdarΔ2-13 null mutant mouse embryos lacking ADAR1 protein die with high levels of IFN-stimulated gene (ISG) transcripts. In Adar Mavs double mutants also lacking the Mitochondrial antiviral signalling (MAVS) adaptor, the aberrant IFN induction is prevented. Live pups are born and survive for 2 weeks, allowing ADAR1 function to be investigated. We have shown that early death of Adar Mavs mutants is rescued by the deletion of the Eif2ak2 gene encoding the antiviral dsRNA sensor protein kinase R (PKR). Here, we focused on characterizing the brain defects in Adar Mavs mutants and their dependencies on PKR. Mouse brains were collected on postnatal Days 8 and 14, then analysed by mass spectrometry, immunohistochemistry and RT-qPCR. The proteomic analyses showed upregulation of ISG-encoded proteins in the Adar Mavs double mutant, and the morphological analyses confirmed aberrant microgliosis in the brains. Both are prevented in Adar Mavs Eif2ak2 triple mutants, indicating the key role of aberrant PKR activation; PKR expression is also increased by IFN signalling. Altered expression levels of transcripts encoding differentially expressed proteins and of ADAR-edited transcripts were confirmed by RT-qPCR. Analysis of the expression levels of transcripts in the brains of mutants expressing a catalytically inactive ADAR E861A protein revealed that the levels of some but not all altered transcripts are restored. A further group of proteins, downregulated in Adar Mavs double mutants, are not rescued by removal of PKR and might result from effects of loss of the widespread ADAR1 RNA editing known to occur in brain transcripts. This group includes several motor proteins, some of which have been reported to be encoded by ADAR-edited transcripts. In this study, we show that Adar Mavs double mutants exhibit an aberrant IFN response in the brain, probably attributable to reactive microglia and astrocytes. Microgliosis, which is rescued in the triple mutant, is mostly dependent on aberrant PKR activation and is partly dependent on RNA editing.
2025-08-01 | Dual pathology of parvovirus B19 infection and Aicardi-Goutières syndrome complicating non-immune hydrops fetalis.
Non-immune hydrops fetalis (NIHF) is a multifactorial condition characterised by abnormal fluid accumulation in fetal compartments. We report a complex case of NIHF in a primigravida in her 30s with dual pathology involving fetal parvovirus B19 infection and Aicardi-Goutières syndrome (AGS) due to a TREX1 gene mutation. The fetus exhibited severe anaemia, hydrops fetalis, ventriculomegaly and brain calcifications. Whole exome sequencing confirmed AGS as the genetic aetiology, while PCR on amniotic fluid identified parvovirus B19 as a coexisting infection. Although AGS alone has varied phenotype and prognosis but due to coexisting severe anaemia, the neonate succumbed postnatally. This report highlights the importance of integrating genetic and infectious workups in atypical NIHF cases.
2025-04-21 | Aicardi-Goutières Syndrome Associated ADAR G1007R mutation dominantly induces neuroinflammation in mouse brain
Abstract The ADAR G 1007 R mutation is one of the most frequent mutations found in type six Aicardi-Goutières Syndrome (AGS), a severe inflammatory encephalopathy in pediatric patients. We report here a mouse model bearing an human equivalent ADAR G 1007 R mutation, and the heterozygous mice recapitulated some pathologic features of ADAR G 1007 R AGS patients, including early-onset brain inflammation in heterozygous individuals and interferon-stimulated gene (ISG) expression within deep brain areas. Furthermore, we demonstrated that brain inflammation could be reversed by deletion of the cellular RNA receptor MDA5, which blocks the cellular RNA sensing signaling pathway. This model provides a unique tool for studying the molecular mechanisms underlying the heterozygous ADAR WT/G 1007 R mutation in AGS brain pathogenesis. It may also be a valuable platform for developing personalized therapies for patients with this specific mutation.
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2026-01-27 | Author response: Microglia replacement by ER-Hoxb8 conditionally immortalized macrophages provides insight into Aicardi–Goutières syndrome neuropathology
A microglia replacement approach demonstrates that brain macrophages with patient mutations from Aicardi–Goutières syndrome, a genetic, brain predominant interferonopathy, are sufficient to drive interferon responses.
2026-01-27 | Basic Microglial Functions and How They Go Awry in Neurodegenerative Disease.
Microglia-the parenchymal tissue-resident macrophages of the brain and spinal cord-are essential to support brain health by integrating environmental cues and performing immune functions and reparative processes. Yet across neurodegenerative diseases, these long-lived cells become increasingly unable to meet the demands of their homeostatic roles. In this review, we trace the arc of microglial function from competence to dysfunction, examining how their roles, for example, in synaptic pruning, phagocytosis, and interferon signaling, can shift from protective to pathogenic. Using Alzheimer's disease, inherited microgliopathies, and Aicardi-Goutières syndrome as case studies, we highlight the ways in which microglia fail-through metabolic exhaustion, lysosomal overload, inflammatory gain of function, or failure to respond. We consider how genetic and environmental factors converge to drive this "microglial incompetence," and discuss emerging strategies to reset or replace dysfunctional microglia. Understanding when and how microglia go awry may unlock new paths for treating a wide spectrum of neurodegenerative diseases.
2026-01-10 | Microglia replacement by ER-Hoxb8 conditionally immortalized macrophages provides insight into Aicardi–Goutières syndrome neuropathology
Microglia, the brain’s resident macrophages, can be reconstituted by surrogate cells – a process termed ‘microglia replacement’. To expand the microglia replacement toolkit, we here introduce estrogen-regulated (ER) homeobox B8 (Hoxb8) conditionally immortalized macrophages, a cell model for generation of immune cells from murine bone marrow, as a versatile model for microglia replacement. We find that ER-Hoxb8 macrophages are highly comparable to primary bone marrow-derived macrophages in vitro, and, when transplanted into a microglia-free brain, engraft the parenchyma and differentiate into microglia-like cells. Furthermore, ER-Hoxb8 progenitors are readily transducible by virus and easily stored as stable, genetically manipulated cell lines. As a demonstration of this system’s power for studying the effects of disease mutations on microglia in vivo, we created stable, Adar1-mutated ER-Hoxb8 lines using CRISPR-Cas9 to study the intrinsic contribution of macrophages to Aicardi–Goutières syndrome (AGS), an inherited interferonopathy that primarily affects the brain and immune system. We find that Adar1 knockout elicited interferon secretion and impaired macrophage production in vitro, while preventing brain macrophage engraftment in vivo – phenotypes that can be rescued with concurrent mutation of Ifih1 (MDA5) in vitro, but not in vivo. Lastly, we extended these findings by generating ER-Hoxb8 progenitors from mice harboring a patient-specific Adar1 mutation (D1113H). We demonstrated the ability of microglia-specific D1113H mutation to drive interferon production in vivo, suggesting microglia drive AGS neuropathology. In sum, we introduce the ER-Hoxb8 approach to model microglia replacement and use it to clarify macrophage contributions to AGS.
2025-07-03 | Deep Brain Stimulation in a Child with Aicardi‐Goutières Syndrome‐7 ( AGS7 ): A Case Report and Literature Review
Aicardi-Goutières syndrome (AGS) is a clinically and genetically heterogeneous group of disorders with neurological and systemic findings.Some individuals present with early-onset encephalopathy, whereas others exhibit normal development followed by regression of milestones.Other signs include intellectual disability, irritability, spasticity, dystonia, acquired microcephaly, sterile pyrexia, chilblains, and hepatosplenomegaly. 1 AGS is caused by homozygous variants in ADAR (OMIM: 146920), RNASEH2A (OMIM: 606034), RNASEH2B (OMIM: 610326), RNASEH2C (OMIM: 610330), SAMHD1 (OMIM; 606754), TREX1 (OMIM: 606609), RNU7-1 (OMIM: 617876), or LSM11 (OMIM: 617910) genes and heterozygous pathogenic variants in TREX1, ADAR, or IFIH1 (OMIM: 606951) genes.1,2 Here we describe a child with AGS7 who had progressive dystonia and was managed with deep brain stimulation (DBS).An 8.5-year-old girl born to nonconsanguineous parents was referred for the management of progressive dystonia and regression of milestones.The mother reported fetal hypokinesia.The baby was born full term by vacuum-assisted delivery with a birth weight of 3150 g, and the neonatal transition was uneventful.Her motor milestones were mildly delayed from 6 months of age.She had a gradual regression of milestones from 18 months of age.Assessment at 21 months of age revealed normocephaly, spasticity of all four limbs, brisk deep tendon reflexes, bilateral ankle clonus, and dystonia of bilateral lower limbs.Brain magnetic resonance imaging (MRI) at 2 years of age (Fig. S1A-F )
2025-06-30 | eLife Assessment: Microglia replacement by ER-Hoxb8 conditionally immortalized macrophages provides insight into Aicardi-Goutières Syndrome neuropathology
Microglia, the brain’s resident macrophages, can be reconstituted by surrogate cells - a process termed “microglia replacement.” To expand the microglia replacement toolkit, we here introduce estrogen-regulated (ER) homeobox B8 (Hoxb8) conditionally immortalized macrophages, a cell model for generation of immune cells from murine bone marrow, as a versatile model for microglia replacement. We find that ER-Hoxb8 macrophages are highly comparable to primary bone marrow-derived (BMD) macrophages in vitro, and, when transplanted into a microglia-free brain, engraft the parenchyma and differentiate into microglia-like cells. Furthermore, ER-Hoxb8 progenitors are readily transducible by virus and easily stored as stable, genetically manipulated cell lines. As a demonstration of this system’s power for studying the effects of disease mutations on microglia in vivo, we created stable, Adar1-mutated ER-Hoxb8 lines using CRISPR-Cas9 to study the intrinsic contribution of macrophages to Aicardi-Goutières Syndrome (AGS), an inherited interferonopathy that primarily affects the brain and immune system. We find that Adar1 knockout elicited interferon secretion and impaired macrophage production in vitro, while preventing brain macrophage engraftment in vivo - phenotypes that can be rescued with concurrent mutation of Ifih1 (MDA5) in vitro, but not in vivo. Lastly, we extended these findings by generating ER-Hoxb8 progenitors from mice harboring a patient-specific Adar1 mutation (D1113H). We demonstrated the ability of microglia-specific D1113H mutation to drive interferon production in vivo, suggesting microglia drive AGS neuropathology. In sum, we introduce the ER-Hoxb8 approach to model microglia replacement and use it to clarify macrophage contributions to AGS.
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Drug Discovery Landscape
3 orphan drug designations for Aicardi-Goutières syndrome.
3 orphan drug designations for Aicardi-Goutières syndrome.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
non-covalent competitive cGAS inhibitor | small molecules | FDA | ImmuneSensor Therapeutics | |
Tenofovir disoproxil fumarate | small molecules | EMA | — | Dr Yanick Crow |
Emtricitabine | small molecules | EMA | — | Dr Yanick Crow |
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