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
323 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:
323 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:
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.
2026-07-28 | 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)
2026-07-22 | Case of Aicardi-Goutières syndrome diagnosed in adulthood on whole-genome sequencing.
Background: Aicardi-Goutières syndrome (AGS) is a neurogenetic leukoencephalopathy that typically manifests within the first 6 months of life. Classically, AGS presents with an early encephalopathic episode characterised by feeding difficulties, irritability and psychomotor regression or delay. Cutaneous lesions affecting the extremities and epilepsy are common, with symptoms usually evolving over weeks to months before stabilising. Milder phenotypes have been described, often demonstrating relative preservation of language and cognitive function. Case presentation: Here, we report a case of a 31-year-old woman with compound heterozygous variants in the ADAR gene: (GRCh38) NM_001111.4:c.577C>G p.(Pro193Ala) and (GRCh38) NM_001111.4:c.1111_1112del p.(Ser371Cysfs*3), consistent with AGS. The developmental history revealed normal early motor milestones. At age 3, she developed progressive ataxia and hypotonia. Over time, she exhibited spasticity, dystonia and learning difficulties, along with significant cardiac valvular calcification. Conclusions: The patient was recently referred for consideration of treatment with baricitinib, a selective JAK1/JAK2 inhibitor. This case underscores the importance of considering AGS in individuals with non-classical presentations, particularly when extracerebral calcification is a notable feature.
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.
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.
2026-07-28 | 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)
2026-07-22 | Case of Aicardi-Goutières syndrome diagnosed in adulthood on whole-genome sequencing.
Background: Aicardi-Goutières syndrome (AGS) is a neurogenetic leukoencephalopathy that typically manifests within the first 6 months of life. Classically, AGS presents with an early encephalopathic episode characterised by feeding difficulties, irritability and psychomotor regression or delay. Cutaneous lesions affecting the extremities and epilepsy are common, with symptoms usually evolving over weeks to months before stabilising. Milder phenotypes have been described, often demonstrating relative preservation of language and cognitive function. Case presentation: Here, we report a case of a 31-year-old woman with compound heterozygous variants in the ADAR gene: (GRCh38) NM_001111.4:c.577C>G p.(Pro193Ala) and (GRCh38) NM_001111.4:c.1111_1112del p.(Ser371Cysfs*3), consistent with AGS. The developmental history revealed normal early motor milestones. At age 3, she developed progressive ataxia and hypotonia. Over time, she exhibited spasticity, dystonia and learning difficulties, along with significant cardiac valvular calcification. Conclusions: The patient was recently referred for consideration of treatment with baricitinib, a selective JAK1/JAK2 inhibitor. This case underscores the importance of considering AGS in individuals with non-classical presentations, particularly when extracerebral calcification is a notable feature.
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.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
3 orphan drug designations for Aicardi-Goutières syndrome.
3 orphan drug designations for Aicardi-Goutières syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
non-covalent competitive cGAS inhibitor | small molecules | FDA | 2024-09-25 | — | ImmuneSensor Therapeutics |
Tenofovir disoproxil fumarate | small molecules | EMA | 2015-01-15 | — | Dr Yanick Crow |
Emtricitabine | small molecules | EMA | 2015-01-15 | — | Dr Yanick Crow |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI's forecasts to outperform average preclinical success rates. Whether you're expanding your R&D pipeline, evaluating a partnership, or simply have a question — we'd love to hear from you.