RARE DISEASE
Aicardi syndrome
Aicardi syndrome
Aicardi syndrome
Synonyms: Agenesis of corpus callosum with chorioretinal abnormality
Synonyms: Agenesis of corpus callosum with chorioretinal abnormality
Synonyms: Agenesis of corpus callosum with chorioretinal abnormality
Drug discovery
139
papers
On emerging therapies
Overview
Aicardi syndrome is a rare neurodevelopmental disorder primarily affecting females, characterized by the classic triad of corpus callosum agenesis, chorioretinal lacunae, and infantile epileptic spasms. Additional features include cortical malformations, severe developmental delay, and scoliosis. While X-linked inheritance is suspected due to female predominance, no causative gene has been identified [1][5][12]. Management focuses on seizure control and multidisciplinary support.
Therapies
Seizure management: Adrenocorticotropic hormone, vigabatrin, ketogenic diet, and vagus nerve stimulation for refractory epilepsy [2][13][17]
Developmental support: Early intervention with physical, occupational, and speech therapies [8][13]
Complication prevention: Scoliosis monitoring, infection prophylaxis, and gastrostomy for feeding difficulties [2][6][13]
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare neoplastic diseases, rare neurological diseases, rare ophthalmic disorders
Research Papers
139 drug discovery papers about Aicardi syndrome, with 1 first-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
139 drug discovery papers about Aicardi syndrome, with 1 first-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
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.
2026-07-01 | Dual Targeting of TBK1 and JAK-STAT1 Pathways by (-)-epigallocatechin-3-gallate Suppresses Type I Interferon-driven Inflammation
Objective Type I interferon (IFN-I) signaling is essential for antiviral innate immunity, yet its sustained or excessive activation contributes to the pathogenesis of several autoimmune diseases and interferonopathies, such as systemic lupus erythematosus and Aicardi-Goutières syndrome. Current strategies targeting this pathway, exemplified by JAK inhibitors, act mainly on downstream signal transduction and provide limited direct control over upstream IFN-I production, while also carrying the risk of broad immunosuppression. Phyllanthus emblica L. has long been used in traditional medicine for inflammatory disorders, but the bioactive constituent responsible for its regulation of IFN-I signaling and the underlying molecular mechanism have not been clearly defined. This study aimed to identify the active anti-inflammatory component of P. emblica and to characterize its mechanism of action on the IFN-I pathway in macrophages. Methods Active components of P. emblica and their candidate targets were screened by network pharmacology using the TCMSP and DrugBank databases (oral bioavailability≥30%, drug-likeness≥0.18) and intersected with inflammation-related genes retrieved from public databases. The predicted interaction between EGCG and IFN-I pathway proteins (TBK1, IRF3, STAT1) was evaluated by molecular docking, with BX795 and GSK8612 used as reference TBK1 inhibitors. Mechanistic experiments were performed in THP-1-derived macrophages and primary bone marrow-derived macrophages (BMDM). Upstream signaling was activated by transfection of the nucleic acid analogs poly(I∶C) and poly(dA∶dT) or by lipopolysaccharide (LPS) stimulation, whereas downstream signaling was activated by exogenous IFN-β. An siRNA-mediated TREX1 knockdown model was used to mimic endogenous nucleic acid-driven interferonopathy. Expression of IFN-β1 and interferon-stimulated genes (ISGs) was measured by RT-qPCR, protein phosphorylation by Western blot, and IFN-β secretion by ELISA. Cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) were used to probe the interaction between EGCG and IRF3. Results Network pharmacology identified (-)-epigallocatechin-3-gallate (EGCG) as a candidate IFN-I-suppressive constituent of P. emblica, with predicted binding to TBK1, IRF3, and STAT1. Molecular docking yielded binding energies of -9.2, -7.2, and -8.2 kcal/mol for TBK1, IRF3, and STAT1, respectively, indicating an affinity for TBK1 comparable to that of the reference inhibitors BX795 (-5.7 kcal/mol) and GSK8612 (-6.4 kcal/mol). EGCG suppressed IFN-β1 and ISG mRNA expression under poly (I∶C), poly (dA∶dT), and LPS stimulation in both THP-1 macrophages and BMDM. At the protein level, EGCG reduced the phosphorylation of TBK1 and IRF3 without affecting the levels of the upstream sensors cGAS and RIG-I, and lowered IFN-β secretion in a concentration-dependent manner. CETSA and DARTS showed that EGCG did not enhance the thermal stability or protease resistance of IRF3, indicating that its effect on IRF3 is indirect. Following IFN-β stimulation, prolonged EGCG treatment reduced STAT1 phosphorylation in a time-dependent manner without an apparent change in IRF9, and partially attenuated ISG transcription; this effect was not monotonicly concentration-dependent, and CXCL10 showed the most consistent suppression. In TREX1-knockdown cells, the elevated mRNA levels of ISG15, ISG56, and CXCL10 were reduced by EGCG. Conclusion EGCG suppresses IFN-I responses by concurrently inhibiting TBK1-IRF3-dependent IFN‑β production and JAK-STAT1-mediated downstream transcription. These in vitro findings provide a mechanistic basis for the anti-inflammatory use of P. emblica in traditional medicine and identify EGCG as a candidate for further evaluation in interferon-driven autoimmune disease models.
2026-06-30 | JAK Inhibition in PNPT1-Related Mitochondrial Interferonopathy: A Case Report and Review of Mitochondrial-Immune Crosstalk.
Biallelic pathogenic variants in PNPT1 cause combined oxidative phosphorylation deficiency 13 (COXPD13) (MIM #614932), linking mitochondrial dysfunction to type I interferon (IFN) activation through cytosolic leakage of mitochondrial double-stranded RNA (mt-dsRNA). This mechanism connects mitochondrial disease to interferonopathies such as Aicardi-Goutières syndrome (AGS). We describe a 7-month-old female infant with compound heterozygous PNPT1 variants presenting with severe hypotonia, feeding difficulties necessitating gastrostomy, dystonia, and elevated serum lactate. Brain magnetic resonance imaging (MRI) demonstrated marked cerebellar, brainstem, and basal ganglia atrophy, with a lactate peak on MR spectroscopy (consistent with an inverted doublet). Serum immune profiling revealed a mild but elevated type I IFN signature. Given the mechanistic overlap with AGS, off-label tofacitinib, a Janus kinase (JAK) inhibitor that blocks IFN-driven JAK/STAT signaling, was initiated following pediatric interferonopathy dosing protocols. Tofacitinib was associated with normalization of serum type I IFN biomarkers, reduction in lactate and transaminases, improvement in dystonic movements, ventilatory stability, and improved growth/nutrition without treatment-limiting adverse events. To our knowledge, this represents the first reported use of JAK inhibition in COXPD13. The observed clinical and biochemical stabilization supports defining COXPD13 as a "mitochondrial interferonopathy" and suggests that IFN-signature screening may identify mitochondrial disease patients who could benefit from targeted immunomodulation.
oligonucleotides
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.
2022-12-01 | An AGS-associated mutation in ADAR1 catalytic domain results in early-onset and MDA5-dependent encephalopathy with IFN pathway activation in the brain
Aicardi-Goutières syndrome (AGS) is a severe neurodegenerative disease with clinical features of early-onset encephalopathy and progressive loss of intellectual abilities and motor control. Gene mutations in seven protein-coding genes have been found to be associated with AGS. However, the causative role of these mutations in the early-onset neuropathogenesis has not been demonstrated in animal models, and the mechanism of neurodegeneration of AGS remains ambiguous.Via CRISPR/Cas-9 technology, we established a mutant mouse model in which a genetic mutation found in AGS patients at the ADAR1 coding gene (Adar) loci was introduced into the mouse genome. A mouse model carrying double gene mutations encoding ADAR1 and MDA-5 was prepared using a breeding strategy. Phenotype, gene expression, RNA sequencing, innate immune pathway activation, and pathologic studies including RNA in situ hybridization (ISH) and immunohistochemistry were used for characterization of the mouse models to determine potential disease mechanisms.We established a mouse model bearing a mutation in the catalytic domain of ADAR1, the D1113H mutation found in AGS patients. With this mouse model, we demonstrated a causative role of this mutation for the early-onset brain injuries in AGS and determined the signaling pathway underlying the neuropathogenesis. First, this mutation altered the RNA editing profile in neural transcripts and led to robust IFN-stimulated gene (ISG) expression in the brain. By ISH, the brains of mutant mice showed an unusual, multifocal increased expression of ISGs that was cell-type dependent. Early-onset astrocytosis and microgliosis and later stage calcification in the deep white matter areas were observed in the mutant mice. Brain ISG activation and neuroglial reaction were completely prevented in the Adar D1113H mutant mice by blocking RNA sensing through deletion of the cytosolic RNA receptor MDA-5.The Adar D1113H mutation in the ADAR1 catalytic domain results in early-onset and MDA5-dependent encephalopathy with IFN pathway activation in the mouse brain.
2021-10-28 | RNA sensing via LGP2 is essential for the induction of a type I IFN response in ADAR1 deficiency
Abstract RNA editing by the enzyme Adenosine Deaminase Acting on RNA 1 (ADAR1) is an important mechanism by which cells avoid innate immune responses to some endogenous RNAs. In ADAR1-deficient cells, unedited self RNAs can form base-paired structures that resemble viral RNAs and inadvertently activate antiviral innate immune pathways that lead to the induction of type I interferon (IFN). Rare mutations in ADAR1 cause Aicardi-Goutières Syndrome (AGS), a severe childhood autoinflammatory syndrome that is characterized by chronic and excessive type I IFN production and developmental delay. Conversely, ADAR1 dysfunction and consequent type I IFN production helps restrict tumor growth and potentiates the activity of some chemotherapy drugs. Induction of type I IFN in ADAR1-deficient cells is thought to be due to triggering of the cytosolic RIG-I-like receptor (RLR), MDA5, by unedited self RNAs. Here, we show that another RLR, LGP2, also has an essential role. We demonstrate that ADAR1-deficient human cells fail to mount a type I IFN response in the absence of LGP2 and this involves the canonical function of LGP2 as an RNA sensor and facilitator of MDA5-dependent signaling. Further, we show that the sensitivity of tumor cells to ADAR1 loss requires the presence of LGP2. Finally, we find that type I IFN induction in tumor cells depleted of ADAR1 and treated with some chemotherapeutics is fully dependent on the expression of LGP2. These findings highlight a central role for LGP2 in self RNA sensing with important clinical implications for the treatment of AGS as well as for the potential application of ADAR1-directed anti-tumor therapy.
2018-04-11 | Prevention of Lymphocyte Neurotoxic Effects by microRNA Delivery.
Aicardi Goutieres Syndrome (AGS) is characterized by mutations occurring in genes encoding RNAses. AGS mutations silence intracellular RNases resulting in an intracellular overload of short RNAs arresting the physiological production of microRNA required for brain development. MiR-219 is typically down-regulated in Aicardi Goutieres Syn-drome (AGS). The goal of this study is to investigate miR-219 role in protecting astrocytes co-cultured with AGS-mutated lymphocytes. These lymphocytes display neurotoxic properties due to the presence of AGS-mutation and to their activa-tion by interpheron-alpha (IFN). Obtained results provide the evidence that astrocytes transfected with microRNA-219 are protected from the neurotoxic action of AGS lymphocytes activated by IFN-alpha. In particular, the miR-219 transfection increased astrocyte viability, growth, and differentiation while decreasing cell necrosis and apoptosis. Thus, microRNA-219 transfection is a valuable strategy in order to confer resistance to astrocytes towards lymphocyte-induced neurotoxici-ty especially in the presence of IFN-alpha, whose levels are typically increased in the cerebrospinal fluid of AGS patients.
2017-12-07 | Suppressive oligodeoxynucleotides containing TTAGGG motifs inhibit cGAS activation in human monocytes
Abstract Type I interferon (IFN) is a critical mediator of autoimmune diseases such as systemic lupus erythematosus (SLE) and Aicardi–Goutières Syndrome (AGS). The recently discovered cyclic‐GMP‐AMP (cGAMP) synthase (cGAS) induces the production of type I IFN in response to cytosolic DNA and is potentially linked to SLE and AGS. Suppressive oligodeoxynucleotides (ODN) containing repetitive TTAGGG motifs present in mammalian telomeres have proven useful in the treatment of autoimmune diseases including SLE. In this study, we demonstrate that the suppressive ODN A151 effectively inhibits activation of cGAS in response to cytosolic DNA, thereby inhibiting type I IFN production by human monocytes. In addition, A151 abrogated cGAS activation in response to endogenous accumulation of DNA using TREX1‐deficient monocytes. We demonstrate that A151 prevents cGAS activation in a manner that is competitive with DNA. This suppressive activity of A151 was dependent on both telomeric sequence and phosphorothioate backbone. To our knowledge this report presents the first cGAS inhibitor capable of blocking self‐DNA. Collectively, these findings might lead to the development of new therapeutics against IFN‐driven pathologies due to cGAS activation.
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)
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.
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.
2022-04-12 | RNA sensor MDA5 suppresses LINE-1 retrotransposition by regulating the promoter activity of LINE-1 5′-UTR
Abstract Background Type 1 long interspersed elements, or LINE-1, are the only retroelements that replicate autonomously in human cells. The retrotransposition process of LINE-1 can trigger the activation of the innate immune system and has been proposed to play a role in the development of several autoimmune diseases, including Aicardi-Goutières syndrome (AGS). In contrast, all known AGS-associated proteins, except MDA5, have been reported to affect LINE-1 activity. Thus, MDA5 is likely to also function as a LINE-1 suppressor. Results MDA5 was found to potently suppress LINE-1 activity in a reporter-based LINE-1 retrotransposition assay. Although MDA5 is an endogenous RNA sensor able to activate the innate immune system, increased interferon (IFN) expression only contributed in part to MDA5-mediated LINE-1 suppression. Instead, MDA5 potently regulated the promoter activity of LINE-1 5′-UTR, as confirmed by transiently expressed myc-tagged MDA5 or knockdown of endogenous MDA5 expression. Consequently, MDA5 effectively reduced the generation of LINE-1 RNA and the subsequent expression of LINE-1 ORF1p and ORF2p. Interestingly, despite MDA5 being a multi-domain protein, the N-terminal 2CARD domain alone is sufficient to interact with LINE-1 5′-UTR and inhibit LINE-1 promoter activity. Conclusion Our data reveal that MDA5 functions as a promoter regulator; it directly binds to the LINE-1 5′-UTR and suppresses its promoter activity. Consequently, MDA5 reduces LINE-1 RNA and protein levels, and ultimately inhibits LINE-1 retrotransposition. In contrast, MDA5-induced IFN expression only plays a mild role in MDA5-mediated LINE-1 suppression. In addition, the N-terminal 2CARD domain was found to be a functional region for MDA5 upon inhibition of LINE-1 replication. Thus, our data suggest that besides being an initiator of the innate immune system, MDA5 is also an effector against LINE-1 activity, potentially forming a feedback loop by suppressing LINE-1-induced innate immune activation.
gene therapies
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.
2025-04-21 | 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.
2025-01-28 | Increased interferon I signaling, DNA damage response and evidence of T-cell exhaustion in a patient with combined interferonopathy (Aicardi-Goutières Syndrome, AGS) and cohesinopathy (Cornelia de Lange Syndrome, CdLS).
Type I interferonopathies including Aicardi-Goutiéres Syndrome (AGS) represent a heterogeneous group of clinical phenotypes. Herein, we present a Case with combined AGS and Cornelia de Lange Syndrome (CdLS)-a cohesinopathy-with comprehensive analysis of the immune and genomic abnormalities. A 20-year old man presented with chilblain lesions and resorption of distal phalanges of fingers and toes, somatic and psychomotor retardation, microcephaly, synophrys, hearing losing and other aberrancies consistent with the phenotype of CdLS. We used whole exome sequencing to genetically map the associated mutations and performed transcriptome profiling and enrichment analysis in CD14+ monocytes of the patient and immune phenotyping by mass cytometry (CyToF), comparing to healthy individuals and lupus patients as disease controls. DNA damage response was assayed by confocal microscopy in the peripheral blood of this patient. Next generation exome sequencing confirmed a homozygous SAMHD1 gene mutation and a hemizygous non-synonymous mutation on SMC1A gene, responsible for the AGS and CdLS, respectively. Transcriptome profiling of CD14+ monocytes of the patient showed enrichment of type I IFN signaling and enhanced DNA damage response pathway. Broad immune phenotype of the peripheral blood of the patient revealed absence of activated T cell populations, increased frequency of NK cells and plasmablasts and enhanced granulocytic lineage. Further analysis suggested activation of the ATM branch of DNA damage response and increased apoptosis in the periphery of the patient. A rare case of a patient bearing two genetic lesions (responsible for AGS/CdLS syndromes) exhibits distinctive features of genomic damage and interferon responses. Immune phenotype revealed granulocytic skewing and absence of activated T cells compatible with chronic antigenic stimulation and/or homing of these cells at sites of inflammation.
2024-07-10 | The brain microvasculature is a primary mediator of interferon-α neurotoxicity in human cerebral interferonopathies.
Aicardi-Goutières syndrome (AGS) is an autoinflammatory disease characterized by aberrant interferon (IFN)-α production. The major cause of morbidity in AGS is brain disease, yet the primary source and target of neurotoxic IFN-α remain unclear. Here, we demonstrated that the brain was the primary source of neurotoxic IFN-α in AGS and confirmed the neurotoxicity of intracerebral IFN-α using astrocyte-driven Ifna1 misexpression in mice. Using single-cell RNA sequencing, we demonstrated that intracerebral IFN-α-activated receptor (IFNAR) signaling within cerebral endothelial cells caused a distinctive cerebral small vessel disease similar to that observed in individuals with AGS. Magnetic resonance imaging (MRI) and single-molecule ELISA revealed that central and not peripheral IFN-α was the primary determinant of microvascular disease in humans. Ablation of endothelial Ifnar1 in mice rescued microvascular disease, stopped the development of diffuse brain disease, and prolonged lifespan. These results identify the cerebral microvasculature as a primary mediator of IFN-α neurotoxicity in AGS, representing an accessible target for therapeutic intervention.
other
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.
2025-12-22 | RNASEH2B at the Crossroads: From Aicardi–Goutières Syndrome to Monogenic Lupus
Introduction Biallelic mutations in RNASEH2B are classically associated with Aicardi–Goutières syndrome. However, heterozygous variants have recently been linked to monogenic systemic lupus erythematosus, expanding the clinical spectrum. Case Reports: P1 A 29-year-old male. At age 18, developed chronic severe thrombocytopenia refractory to steroids and rituximab, with multiple hospitalizations for trauma-related bleeding. Later presented with hypothyroidism and chondritis. Labs showed normal immunoglobulins, positive antinuclear antibodies (1:160), low B (260/mm3) and natural killer (NK) cells (58/mm3), high double negative T (DNT) cells (9%), altered T and B subpopulations (high central memory T and DR+ T cells, low switched B cells, and high transitional B cells). Treated with sirolimus and hydroxychloroquine with mild response. With subcutaneous immunoglobulin, achieved platelet and DNT normalization. P2: 14-year-old male. At age 4, presented with urticaria and angioedema on hands, ears, and face, worsened by sun exposure, unresponsive to antihistamines or steroids. Immunologic workup showed no cytopenia, normal acute-phase markers, low IgG (<1/2 SD), normal IgA/IgM, normal complement (C3/C4), negative autoantibodies, and normal lymphocyte subsets (CD3+, CD4+, CD8+, CD19+, CD56+). P3: 27-year-old female. At age 25, presented two events of myopericarditis requiring hospitalization. Extensive cardiac workup confirmed elevated cardiac enzymes with normal imaging, and the patient responded to colchicine, nonsteroidal, anti-inflammatory drugs, and corticosteroids. Immunological studies showed normal immunoglobulins and complement, negative autoantibodies, and NK lymphopenia. All patients carried the heterozygous pathogenic variant RNASEH2B c.529G>A, p.(Ala177Thr). Interferon signature was performed in 2/3 patients and was markedly elevated in P1: 174.48 (cutoff 8.4) and IL-18 at 106.1 copies/ng (reference value <35); and P2: 28.2. P1 is currently on eltrombopag and in plan of starting baricitinib, P2 remains under expectant management, and P3 is receiving colchicine. Discussion These cases highlight that patients with heterozygous variants in RNASEH2B developed clinical symptoms. The elevated interferon signature supports type I interferonopathy as a shared pathophysiological mechanism in these patients. Early recognition is crucial to diagnose and guide targeted treatment.
2025-07-02 | A new archipelago on the horizon: type 1 interferonopathies
Type 1 interferonopathies are rare genetic disorders characterized by abnormal type 1 interferon (IFN) signaling. They cause chronic inflammation and multisystemic symptoms typically present in early childhood. Neurological, dermatological, and musculoskeletal features are common and often resistant to conventional therapies. Mutations in genes involved in nucleic acid sensing, degradation, proteasome function, and IFN signaling lead to the accumulation of self-deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) in the cytoplasm and a sustained type 1 IFN response, causing tissue damage and autoimmunity. This group includes various syndromes, such as Aicardi-Goutières syndrome (AGS), STING-associated vasculopathy (SAVI), and COPA syndrome. Diagnosis involves clinical evaluation, IFN signature analysis, and genetic testing. Treatment aims to modulate the IFN response by using JAK inhibitors, anti-IFN antibodies, and reverse transcriptase inhibitors. However, these therapies are not curative and have limited efficacy. Further research is needed to develop targeted treatments and improve outcomes, and a multidisciplinary management approach is essential because of the complexity and rarity of these disorders.
2022-02-01 | Aicardi-Goutières syndrome-like encephalitis in mutant mice with constitutively active MDA5.
MDA5 is a cytoplasmic sensor of viral RNA, triggering type I interferon (IFN-I) production. Constitutively active MDA5 has been linked to autoimmune diseases such as systemic lupus erythematosus, Singleton-Merten syndrome (SMS) and Aicardi-Goutières syndrome (AGS), a genetically determined inflammatory encephalopathy. However, AGS research is challenging due to the lack of animal models. We previously reported lupus-like nephritis and SMS-like bone abnormalities in adult mice with constitutively active MDA5 (Ifih1G821S/+), and herein demonstrate that these mice also exhibit high lethality and spontaneous encephalitis with high IFN-I production during the early postnatal period. Increases in the number of microglia were observed in MDA5/MAVS signaling- and IFN-I-dependent manners. Furthermore, microglia showed an activated state with an increased phagocytic capability and reduced expression of neurotrophic factors. Although multiple auto-antibodies including lupus-related ones were detected in the sera of the mice as well as AGS patients, Ifih1G821S/+Rag2-/- mice also exhibited up-regulation of IFN-I, astrogliosis and microgliosis, indicating that auto-antibodies or lymphocytes are not required for the development of the encephalitis. The IFN-I signature without lymphocytic infiltration observed in Ifih1G821S/+ mice is a typical feature of AGS. Collectively, our results suggest that the Ifih1G821S/+ mice are a model recapitulating AGS and that microglia are a potential target for AGS therapy.
2020-03-16 | Microglia responses to interleukin-6 and type I interferons in neuroinflammatory disease.
Microglia are the resident macrophages of the central nervous system (CNS). They are a heterogenous, exquisitely responsive, and highly plastic cell population, which enables them to perform diverse roles. They sense and respond to the local production of many different signals, including an assorted range of cytokines. Microglia respond strongly to interleukin-6 (IL-6) and members of the type I interferon (IFN-I) family, IFN-alpha (IFN-α), and IFN-beta (IFN-β). Although these cytokines are essential in maintaining homeostasis and for activating and regulating immune responses, their chronic production has been linked to the development of distinct human neurological diseases, termed "cerebral cytokinopathies." IL-6 and IFN-α have been identified as key mediators in the pathogenesis of neuroinflammatory disorders including neuromyelitis optica and Aicardi-Goutières syndrome, respectively, whereas IFN-β has an emerging role as a causal factor in age-associated cognitive decline. One of the key features that unites these diseases is the presence of highly reactive microglia. The current understanding is that microglia contribute to the development of cerebral cytokinopathies and represent an important therapeutic target. However, it remains to be resolved whether microglia have beneficial or detrimental effects. Here we review and discuss what is currently known about the microglial response to IL-6 and IFN-I, based on both animal models and clinical studies. Foundational knowledge regarding the microglial response to IL-6 and IFN-I is now being used to devise therapeutic strategies to ameliorate neuroinflammation and promote repair: either through targeting microglia, or by targeting the reduction of CNS levels or downstream biological pathways of IL-6 or IFN-I.
small molecules
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.
2026-07-01 | Dual Targeting of TBK1 and JAK-STAT1 Pathways by (-)-epigallocatechin-3-gallate Suppresses Type I Interferon-driven Inflammation
Objective Type I interferon (IFN-I) signaling is essential for antiviral innate immunity, yet its sustained or excessive activation contributes to the pathogenesis of several autoimmune diseases and interferonopathies, such as systemic lupus erythematosus and Aicardi-Goutières syndrome. Current strategies targeting this pathway, exemplified by JAK inhibitors, act mainly on downstream signal transduction and provide limited direct control over upstream IFN-I production, while also carrying the risk of broad immunosuppression. Phyllanthus emblica L. has long been used in traditional medicine for inflammatory disorders, but the bioactive constituent responsible for its regulation of IFN-I signaling and the underlying molecular mechanism have not been clearly defined. This study aimed to identify the active anti-inflammatory component of P. emblica and to characterize its mechanism of action on the IFN-I pathway in macrophages. Methods Active components of P. emblica and their candidate targets were screened by network pharmacology using the TCMSP and DrugBank databases (oral bioavailability≥30%, drug-likeness≥0.18) and intersected with inflammation-related genes retrieved from public databases. The predicted interaction between EGCG and IFN-I pathway proteins (TBK1, IRF3, STAT1) was evaluated by molecular docking, with BX795 and GSK8612 used as reference TBK1 inhibitors. Mechanistic experiments were performed in THP-1-derived macrophages and primary bone marrow-derived macrophages (BMDM). Upstream signaling was activated by transfection of the nucleic acid analogs poly(I∶C) and poly(dA∶dT) or by lipopolysaccharide (LPS) stimulation, whereas downstream signaling was activated by exogenous IFN-β. An siRNA-mediated TREX1 knockdown model was used to mimic endogenous nucleic acid-driven interferonopathy. Expression of IFN-β1 and interferon-stimulated genes (ISGs) was measured by RT-qPCR, protein phosphorylation by Western blot, and IFN-β secretion by ELISA. Cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) were used to probe the interaction between EGCG and IRF3. Results Network pharmacology identified (-)-epigallocatechin-3-gallate (EGCG) as a candidate IFN-I-suppressive constituent of P. emblica, with predicted binding to TBK1, IRF3, and STAT1. Molecular docking yielded binding energies of -9.2, -7.2, and -8.2 kcal/mol for TBK1, IRF3, and STAT1, respectively, indicating an affinity for TBK1 comparable to that of the reference inhibitors BX795 (-5.7 kcal/mol) and GSK8612 (-6.4 kcal/mol). EGCG suppressed IFN-β1 and ISG mRNA expression under poly (I∶C), poly (dA∶dT), and LPS stimulation in both THP-1 macrophages and BMDM. At the protein level, EGCG reduced the phosphorylation of TBK1 and IRF3 without affecting the levels of the upstream sensors cGAS and RIG-I, and lowered IFN-β secretion in a concentration-dependent manner. CETSA and DARTS showed that EGCG did not enhance the thermal stability or protease resistance of IRF3, indicating that its effect on IRF3 is indirect. Following IFN-β stimulation, prolonged EGCG treatment reduced STAT1 phosphorylation in a time-dependent manner without an apparent change in IRF9, and partially attenuated ISG transcription; this effect was not monotonicly concentration-dependent, and CXCL10 showed the most consistent suppression. In TREX1-knockdown cells, the elevated mRNA levels of ISG15, ISG56, and CXCL10 were reduced by EGCG. Conclusion EGCG suppresses IFN-I responses by concurrently inhibiting TBK1-IRF3-dependent IFN‑β production and JAK-STAT1-mediated downstream transcription. These in vitro findings provide a mechanistic basis for the anti-inflammatory use of P. emblica in traditional medicine and identify EGCG as a candidate for further evaluation in interferon-driven autoimmune disease models.
2026-06-30 | JAK Inhibition in PNPT1-Related Mitochondrial Interferonopathy: A Case Report and Review of Mitochondrial-Immune Crosstalk.
Biallelic pathogenic variants in PNPT1 cause combined oxidative phosphorylation deficiency 13 (COXPD13) (MIM #614932), linking mitochondrial dysfunction to type I interferon (IFN) activation through cytosolic leakage of mitochondrial double-stranded RNA (mt-dsRNA). This mechanism connects mitochondrial disease to interferonopathies such as Aicardi-Goutières syndrome (AGS). We describe a 7-month-old female infant with compound heterozygous PNPT1 variants presenting with severe hypotonia, feeding difficulties necessitating gastrostomy, dystonia, and elevated serum lactate. Brain magnetic resonance imaging (MRI) demonstrated marked cerebellar, brainstem, and basal ganglia atrophy, with a lactate peak on MR spectroscopy (consistent with an inverted doublet). Serum immune profiling revealed a mild but elevated type I IFN signature. Given the mechanistic overlap with AGS, off-label tofacitinib, a Janus kinase (JAK) inhibitor that blocks IFN-driven JAK/STAT signaling, was initiated following pediatric interferonopathy dosing protocols. Tofacitinib was associated with normalization of serum type I IFN biomarkers, reduction in lactate and transaminases, improvement in dystonic movements, ventilatory stability, and improved growth/nutrition without treatment-limiting adverse events. To our knowledge, this represents the first reported use of JAK inhibition in COXPD13. The observed clinical and biochemical stabilization supports defining COXPD13 as a "mitochondrial interferonopathy" and suggests that IFN-signature screening may identify mitochondrial disease patients who could benefit from targeted immunomodulation.
oligonucleotides
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.
2022-12-01 | An AGS-associated mutation in ADAR1 catalytic domain results in early-onset and MDA5-dependent encephalopathy with IFN pathway activation in the brain
Aicardi-Goutières syndrome (AGS) is a severe neurodegenerative disease with clinical features of early-onset encephalopathy and progressive loss of intellectual abilities and motor control. Gene mutations in seven protein-coding genes have been found to be associated with AGS. However, the causative role of these mutations in the early-onset neuropathogenesis has not been demonstrated in animal models, and the mechanism of neurodegeneration of AGS remains ambiguous.Via CRISPR/Cas-9 technology, we established a mutant mouse model in which a genetic mutation found in AGS patients at the ADAR1 coding gene (Adar) loci was introduced into the mouse genome. A mouse model carrying double gene mutations encoding ADAR1 and MDA-5 was prepared using a breeding strategy. Phenotype, gene expression, RNA sequencing, innate immune pathway activation, and pathologic studies including RNA in situ hybridization (ISH) and immunohistochemistry were used for characterization of the mouse models to determine potential disease mechanisms.We established a mouse model bearing a mutation in the catalytic domain of ADAR1, the D1113H mutation found in AGS patients. With this mouse model, we demonstrated a causative role of this mutation for the early-onset brain injuries in AGS and determined the signaling pathway underlying the neuropathogenesis. First, this mutation altered the RNA editing profile in neural transcripts and led to robust IFN-stimulated gene (ISG) expression in the brain. By ISH, the brains of mutant mice showed an unusual, multifocal increased expression of ISGs that was cell-type dependent. Early-onset astrocytosis and microgliosis and later stage calcification in the deep white matter areas were observed in the mutant mice. Brain ISG activation and neuroglial reaction were completely prevented in the Adar D1113H mutant mice by blocking RNA sensing through deletion of the cytosolic RNA receptor MDA-5.The Adar D1113H mutation in the ADAR1 catalytic domain results in early-onset and MDA5-dependent encephalopathy with IFN pathway activation in the mouse brain.
2021-10-28 | RNA sensing via LGP2 is essential for the induction of a type I IFN response in ADAR1 deficiency
Abstract RNA editing by the enzyme Adenosine Deaminase Acting on RNA 1 (ADAR1) is an important mechanism by which cells avoid innate immune responses to some endogenous RNAs. In ADAR1-deficient cells, unedited self RNAs can form base-paired structures that resemble viral RNAs and inadvertently activate antiviral innate immune pathways that lead to the induction of type I interferon (IFN). Rare mutations in ADAR1 cause Aicardi-Goutières Syndrome (AGS), a severe childhood autoinflammatory syndrome that is characterized by chronic and excessive type I IFN production and developmental delay. Conversely, ADAR1 dysfunction and consequent type I IFN production helps restrict tumor growth and potentiates the activity of some chemotherapy drugs. Induction of type I IFN in ADAR1-deficient cells is thought to be due to triggering of the cytosolic RIG-I-like receptor (RLR), MDA5, by unedited self RNAs. Here, we show that another RLR, LGP2, also has an essential role. We demonstrate that ADAR1-deficient human cells fail to mount a type I IFN response in the absence of LGP2 and this involves the canonical function of LGP2 as an RNA sensor and facilitator of MDA5-dependent signaling. Further, we show that the sensitivity of tumor cells to ADAR1 loss requires the presence of LGP2. Finally, we find that type I IFN induction in tumor cells depleted of ADAR1 and treated with some chemotherapeutics is fully dependent on the expression of LGP2. These findings highlight a central role for LGP2 in self RNA sensing with important clinical implications for the treatment of AGS as well as for the potential application of ADAR1-directed anti-tumor therapy.
2018-04-11 | Prevention of Lymphocyte Neurotoxic Effects by microRNA Delivery.
Aicardi Goutieres Syndrome (AGS) is characterized by mutations occurring in genes encoding RNAses. AGS mutations silence intracellular RNases resulting in an intracellular overload of short RNAs arresting the physiological production of microRNA required for brain development. MiR-219 is typically down-regulated in Aicardi Goutieres Syn-drome (AGS). The goal of this study is to investigate miR-219 role in protecting astrocytes co-cultured with AGS-mutated lymphocytes. These lymphocytes display neurotoxic properties due to the presence of AGS-mutation and to their activa-tion by interpheron-alpha (IFN). Obtained results provide the evidence that astrocytes transfected with microRNA-219 are protected from the neurotoxic action of AGS lymphocytes activated by IFN-alpha. In particular, the miR-219 transfection increased astrocyte viability, growth, and differentiation while decreasing cell necrosis and apoptosis. Thus, microRNA-219 transfection is a valuable strategy in order to confer resistance to astrocytes towards lymphocyte-induced neurotoxici-ty especially in the presence of IFN-alpha, whose levels are typically increased in the cerebrospinal fluid of AGS patients.
2017-12-07 | Suppressive oligodeoxynucleotides containing TTAGGG motifs inhibit cGAS activation in human monocytes
Abstract Type I interferon (IFN) is a critical mediator of autoimmune diseases such as systemic lupus erythematosus (SLE) and Aicardi–Goutières Syndrome (AGS). The recently discovered cyclic‐GMP‐AMP (cGAMP) synthase (cGAS) induces the production of type I IFN in response to cytosolic DNA and is potentially linked to SLE and AGS. Suppressive oligodeoxynucleotides (ODN) containing repetitive TTAGGG motifs present in mammalian telomeres have proven useful in the treatment of autoimmune diseases including SLE. In this study, we demonstrate that the suppressive ODN A151 effectively inhibits activation of cGAS in response to cytosolic DNA, thereby inhibiting type I IFN production by human monocytes. In addition, A151 abrogated cGAS activation in response to endogenous accumulation of DNA using TREX1‐deficient monocytes. We demonstrate that A151 prevents cGAS activation in a manner that is competitive with DNA. This suppressive activity of A151 was dependent on both telomeric sequence and phosphorothioate backbone. To our knowledge this report presents the first cGAS inhibitor capable of blocking self‐DNA. Collectively, these findings might lead to the development of new therapeutics against IFN‐driven pathologies due to cGAS activation.
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)
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.
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.
2022-04-12 | RNA sensor MDA5 suppresses LINE-1 retrotransposition by regulating the promoter activity of LINE-1 5′-UTR
Abstract Background Type 1 long interspersed elements, or LINE-1, are the only retroelements that replicate autonomously in human cells. The retrotransposition process of LINE-1 can trigger the activation of the innate immune system and has been proposed to play a role in the development of several autoimmune diseases, including Aicardi-Goutières syndrome (AGS). In contrast, all known AGS-associated proteins, except MDA5, have been reported to affect LINE-1 activity. Thus, MDA5 is likely to also function as a LINE-1 suppressor. Results MDA5 was found to potently suppress LINE-1 activity in a reporter-based LINE-1 retrotransposition assay. Although MDA5 is an endogenous RNA sensor able to activate the innate immune system, increased interferon (IFN) expression only contributed in part to MDA5-mediated LINE-1 suppression. Instead, MDA5 potently regulated the promoter activity of LINE-1 5′-UTR, as confirmed by transiently expressed myc-tagged MDA5 or knockdown of endogenous MDA5 expression. Consequently, MDA5 effectively reduced the generation of LINE-1 RNA and the subsequent expression of LINE-1 ORF1p and ORF2p. Interestingly, despite MDA5 being a multi-domain protein, the N-terminal 2CARD domain alone is sufficient to interact with LINE-1 5′-UTR and inhibit LINE-1 promoter activity. Conclusion Our data reveal that MDA5 functions as a promoter regulator; it directly binds to the LINE-1 5′-UTR and suppresses its promoter activity. Consequently, MDA5 reduces LINE-1 RNA and protein levels, and ultimately inhibits LINE-1 retrotransposition. In contrast, MDA5-induced IFN expression only plays a mild role in MDA5-mediated LINE-1 suppression. In addition, the N-terminal 2CARD domain was found to be a functional region for MDA5 upon inhibition of LINE-1 replication. Thus, our data suggest that besides being an initiator of the innate immune system, MDA5 is also an effector against LINE-1 activity, potentially forming a feedback loop by suppressing LINE-1-induced innate immune activation.
gene therapies
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.
2025-04-21 | 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.
2025-01-28 | Increased interferon I signaling, DNA damage response and evidence of T-cell exhaustion in a patient with combined interferonopathy (Aicardi-Goutières Syndrome, AGS) and cohesinopathy (Cornelia de Lange Syndrome, CdLS).
Type I interferonopathies including Aicardi-Goutiéres Syndrome (AGS) represent a heterogeneous group of clinical phenotypes. Herein, we present a Case with combined AGS and Cornelia de Lange Syndrome (CdLS)-a cohesinopathy-with comprehensive analysis of the immune and genomic abnormalities. A 20-year old man presented with chilblain lesions and resorption of distal phalanges of fingers and toes, somatic and psychomotor retardation, microcephaly, synophrys, hearing losing and other aberrancies consistent with the phenotype of CdLS. We used whole exome sequencing to genetically map the associated mutations and performed transcriptome profiling and enrichment analysis in CD14+ monocytes of the patient and immune phenotyping by mass cytometry (CyToF), comparing to healthy individuals and lupus patients as disease controls. DNA damage response was assayed by confocal microscopy in the peripheral blood of this patient. Next generation exome sequencing confirmed a homozygous SAMHD1 gene mutation and a hemizygous non-synonymous mutation on SMC1A gene, responsible for the AGS and CdLS, respectively. Transcriptome profiling of CD14+ monocytes of the patient showed enrichment of type I IFN signaling and enhanced DNA damage response pathway. Broad immune phenotype of the peripheral blood of the patient revealed absence of activated T cell populations, increased frequency of NK cells and plasmablasts and enhanced granulocytic lineage. Further analysis suggested activation of the ATM branch of DNA damage response and increased apoptosis in the periphery of the patient. A rare case of a patient bearing two genetic lesions (responsible for AGS/CdLS syndromes) exhibits distinctive features of genomic damage and interferon responses. Immune phenotype revealed granulocytic skewing and absence of activated T cells compatible with chronic antigenic stimulation and/or homing of these cells at sites of inflammation.
2024-07-10 | The brain microvasculature is a primary mediator of interferon-α neurotoxicity in human cerebral interferonopathies.
Aicardi-Goutières syndrome (AGS) is an autoinflammatory disease characterized by aberrant interferon (IFN)-α production. The major cause of morbidity in AGS is brain disease, yet the primary source and target of neurotoxic IFN-α remain unclear. Here, we demonstrated that the brain was the primary source of neurotoxic IFN-α in AGS and confirmed the neurotoxicity of intracerebral IFN-α using astrocyte-driven Ifna1 misexpression in mice. Using single-cell RNA sequencing, we demonstrated that intracerebral IFN-α-activated receptor (IFNAR) signaling within cerebral endothelial cells caused a distinctive cerebral small vessel disease similar to that observed in individuals with AGS. Magnetic resonance imaging (MRI) and single-molecule ELISA revealed that central and not peripheral IFN-α was the primary determinant of microvascular disease in humans. Ablation of endothelial Ifnar1 in mice rescued microvascular disease, stopped the development of diffuse brain disease, and prolonged lifespan. These results identify the cerebral microvasculature as a primary mediator of IFN-α neurotoxicity in AGS, representing an accessible target for therapeutic intervention.
other
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.
2025-12-22 | RNASEH2B at the Crossroads: From Aicardi–Goutières Syndrome to Monogenic Lupus
Introduction Biallelic mutations in RNASEH2B are classically associated with Aicardi–Goutières syndrome. However, heterozygous variants have recently been linked to monogenic systemic lupus erythematosus, expanding the clinical spectrum. Case Reports: P1 A 29-year-old male. At age 18, developed chronic severe thrombocytopenia refractory to steroids and rituximab, with multiple hospitalizations for trauma-related bleeding. Later presented with hypothyroidism and chondritis. Labs showed normal immunoglobulins, positive antinuclear antibodies (1:160), low B (260/mm3) and natural killer (NK) cells (58/mm3), high double negative T (DNT) cells (9%), altered T and B subpopulations (high central memory T and DR+ T cells, low switched B cells, and high transitional B cells). Treated with sirolimus and hydroxychloroquine with mild response. With subcutaneous immunoglobulin, achieved platelet and DNT normalization. P2: 14-year-old male. At age 4, presented with urticaria and angioedema on hands, ears, and face, worsened by sun exposure, unresponsive to antihistamines or steroids. Immunologic workup showed no cytopenia, normal acute-phase markers, low IgG (<1/2 SD), normal IgA/IgM, normal complement (C3/C4), negative autoantibodies, and normal lymphocyte subsets (CD3+, CD4+, CD8+, CD19+, CD56+). P3: 27-year-old female. At age 25, presented two events of myopericarditis requiring hospitalization. Extensive cardiac workup confirmed elevated cardiac enzymes with normal imaging, and the patient responded to colchicine, nonsteroidal, anti-inflammatory drugs, and corticosteroids. Immunological studies showed normal immunoglobulins and complement, negative autoantibodies, and NK lymphopenia. All patients carried the heterozygous pathogenic variant RNASEH2B c.529G>A, p.(Ala177Thr). Interferon signature was performed in 2/3 patients and was markedly elevated in P1: 174.48 (cutoff 8.4) and IL-18 at 106.1 copies/ng (reference value <35); and P2: 28.2. P1 is currently on eltrombopag and in plan of starting baricitinib, P2 remains under expectant management, and P3 is receiving colchicine. Discussion These cases highlight that patients with heterozygous variants in RNASEH2B developed clinical symptoms. The elevated interferon signature supports type I interferonopathy as a shared pathophysiological mechanism in these patients. Early recognition is crucial to diagnose and guide targeted treatment.
2025-07-02 | A new archipelago on the horizon: type 1 interferonopathies
Type 1 interferonopathies are rare genetic disorders characterized by abnormal type 1 interferon (IFN) signaling. They cause chronic inflammation and multisystemic symptoms typically present in early childhood. Neurological, dermatological, and musculoskeletal features are common and often resistant to conventional therapies. Mutations in genes involved in nucleic acid sensing, degradation, proteasome function, and IFN signaling lead to the accumulation of self-deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) in the cytoplasm and a sustained type 1 IFN response, causing tissue damage and autoimmunity. This group includes various syndromes, such as Aicardi-Goutières syndrome (AGS), STING-associated vasculopathy (SAVI), and COPA syndrome. Diagnosis involves clinical evaluation, IFN signature analysis, and genetic testing. Treatment aims to modulate the IFN response by using JAK inhibitors, anti-IFN antibodies, and reverse transcriptase inhibitors. However, these therapies are not curative and have limited efficacy. Further research is needed to develop targeted treatments and improve outcomes, and a multidisciplinary management approach is essential because of the complexity and rarity of these disorders.
2022-02-01 | Aicardi-Goutières syndrome-like encephalitis in mutant mice with constitutively active MDA5.
MDA5 is a cytoplasmic sensor of viral RNA, triggering type I interferon (IFN-I) production. Constitutively active MDA5 has been linked to autoimmune diseases such as systemic lupus erythematosus, Singleton-Merten syndrome (SMS) and Aicardi-Goutières syndrome (AGS), a genetically determined inflammatory encephalopathy. However, AGS research is challenging due to the lack of animal models. We previously reported lupus-like nephritis and SMS-like bone abnormalities in adult mice with constitutively active MDA5 (Ifih1G821S/+), and herein demonstrate that these mice also exhibit high lethality and spontaneous encephalitis with high IFN-I production during the early postnatal period. Increases in the number of microglia were observed in MDA5/MAVS signaling- and IFN-I-dependent manners. Furthermore, microglia showed an activated state with an increased phagocytic capability and reduced expression of neurotrophic factors. Although multiple auto-antibodies including lupus-related ones were detected in the sera of the mice as well as AGS patients, Ifih1G821S/+Rag2-/- mice also exhibited up-regulation of IFN-I, astrogliosis and microgliosis, indicating that auto-antibodies or lymphocytes are not required for the development of the encephalitis. The IFN-I signature without lymphocytic infiltration observed in Ifih1G821S/+ mice is a typical feature of AGS. Collectively, our results suggest that the Ifih1G821S/+ mice are a model recapitulating AGS and that microglia are a potential target for AGS therapy.
2020-03-16 | Microglia responses to interleukin-6 and type I interferons in neuroinflammatory disease.
Microglia are the resident macrophages of the central nervous system (CNS). They are a heterogenous, exquisitely responsive, and highly plastic cell population, which enables them to perform diverse roles. They sense and respond to the local production of many different signals, including an assorted range of cytokines. Microglia respond strongly to interleukin-6 (IL-6) and members of the type I interferon (IFN-I) family, IFN-alpha (IFN-α), and IFN-beta (IFN-β). Although these cytokines are essential in maintaining homeostasis and for activating and regulating immune responses, their chronic production has been linked to the development of distinct human neurological diseases, termed "cerebral cytokinopathies." IL-6 and IFN-α have been identified as key mediators in the pathogenesis of neuroinflammatory disorders including neuromyelitis optica and Aicardi-Goutières syndrome, respectively, whereas IFN-β has an emerging role as a causal factor in age-associated cognitive decline. One of the key features that unites these diseases is the presence of highly reactive microglia. The current understanding is that microglia contribute to the development of cerebral cytokinopathies and represent an important therapeutic target. However, it remains to be resolved whether microglia have beneficial or detrimental effects. Here we review and discuss what is currently known about the microglial response to IL-6 and IFN-I, based on both animal models and clinical studies. Foundational knowledge regarding the microglial response to IL-6 and IFN-I is now being used to devise therapeutic strategies to ameliorate neuroinflammation and promote repair: either through targeting microglia, or by targeting the reduction of CNS levels or downstream biological pathways of IL-6 or IFN-I.
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