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
318 drug discovery papers related to Aicardi-Goutières syndrome, with 4 first-in-class and 4 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
318 drug discovery papers related to Aicardi-Goutières syndrome, with 4 first-in-class and 4 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-04 | Neuron-specific deletion of ADAR1 induces brain malformation and early postnatal lethality.
Adenosine deaminase acting on RNA 1 (ADAR1), which mediates adenosine-to-inosine RNA editing, is expressed as two isoforms, p110 and p150. Deletion of Adar1 p150 in mice results in embryonic lethality caused by aberrant activation of melanoma differentiation-associated protein 5 (MDA5)-mediated sensing of unedited endogenous transcripts, whereas Adar1 p110-specific deficient mice die postnatally through RNA editing-independent mechanisms. ADAR1 mutations cause Aicardi-Goutières syndrome (AGS), a congenital autoinflammatory disease accompanied by encephalopathy with a type I interferon (IFN) signature. However, the roles of ADAR1 in neurons remain elusive. Here, we show that neuron-specific deletion of Adar1 (both p110 and p150) in mice caused early postnatal lethality with elevated expression of type I IFN-stimulated genes (ISGs). Ventricular obstruction due to hypoplasia of the choroid plexus and ependymal cells, which was accompanied by gliosis, was observed. Of note, both selective restoration of ADAR1 p150 function and deletion of MDA5 largely normalized type I ISG expression and ameliorated ventricular obstruction but failed to rescue early postnatal lethality. Furthermore, selective restoration of RNA editing-independent function of ADAR1 p110 was also insufficient to rescue the early postnatal lethality, suggesting that both ADAR1 p110 and p150 in neurons are essential for postnatal survival.
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.
2026-06-30 | Early brain-penetrant immunotherapy reverses interferon signature and improves motor outcome in a case of ADAR1-related Aicardi-Goutières syndrome.
Aicardi-Goutières syndrome (AGS) is a genetic interferonopathy resulting from defects in nucleic acid metabolism and subsequent enhanced type I interferon signalling. We report how an expedited genomic diagnosis in conjunction with natural history data can enable a long-term brain-penetrant anti-inflammatory regimen to optimise neurodevelopmental outcomes in genetic autoinflammatory brain disorders. Expedited genomic testing identified compound heterozygous ADAR1 mutations. Published natural history data from 33 patients with biallelic ADAR1 mutations reported severe disability (GMFCS V) or death in 79%. To reduce neuroinflammation, we commenced a long-term pulsed oral dexamethasone protocol (20 mg/m2 for 3 days every 3 weeks) from the age of 11 months, plus ruxolitinib, a Janus Kinase (JAK) inhibitor (5 mg per day). At the age of 24 months, the patient was crawling and walking a few steps unaided, with a GMFCS level of II. Single-cell RNA sequencing of 41 164 leukocytes, taken before and after 3 months of treatment and compared to three age matched male controls, showed a reversal of upregulated pan-cellular interferon pathways, with most differentially expressed genes observed in monocytes. On treatment, there was statistically significant downregulation of key autoinflammatory genes, including nucleic acid sensing (CGAS, IFIH1, SAMHD1), interferon-stimulated genes (ISG15 and IFIF44L) and signalling (JAK1). Given the dual immune therapy, it was not possible to define whether the biological effect was related to dexamethasone or JAK inhibitor, or both. Compared with natural history data, our data suggest that early diagnosis, and the use of early brain-penetrant immune suppressants (dexamethasone), may improve outcomes in ADAR1 AGS.
2026-07-04 | Neuron-specific deletion of ADAR1 induces brain malformation and early postnatal lethality.
Adenosine deaminase acting on RNA 1 (ADAR1), which mediates adenosine-to-inosine RNA editing, is expressed as two isoforms, p110 and p150. Deletion of Adar1 p150 in mice results in embryonic lethality caused by aberrant activation of melanoma differentiation-associated protein 5 (MDA5)-mediated sensing of unedited endogenous transcripts, whereas Adar1 p110-specific deficient mice die postnatally through RNA editing-independent mechanisms. ADAR1 mutations cause Aicardi-Goutières syndrome (AGS), a congenital autoinflammatory disease accompanied by encephalopathy with a type I interferon (IFN) signature. However, the roles of ADAR1 in neurons remain elusive. Here, we show that neuron-specific deletion of Adar1 (both p110 and p150) in mice caused early postnatal lethality with elevated expression of type I IFN-stimulated genes (ISGs). Ventricular obstruction due to hypoplasia of the choroid plexus and ependymal cells, which was accompanied by gliosis, was observed. Of note, both selective restoration of ADAR1 p150 function and deletion of MDA5 largely normalized type I ISG expression and ameliorated ventricular obstruction but failed to rescue early postnatal lethality. Furthermore, selective restoration of RNA editing-independent function of ADAR1 p110 was also insufficient to rescue the early postnatal lethality, suggesting that both ADAR1 p110 and p150 in neurons are essential for postnatal survival.
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.
2026-06-30 | Early brain-penetrant immunotherapy reverses interferon signature and improves motor outcome in a case of ADAR1-related Aicardi-Goutières syndrome.
Aicardi-Goutières syndrome (AGS) is a genetic interferonopathy resulting from defects in nucleic acid metabolism and subsequent enhanced type I interferon signalling. We report how an expedited genomic diagnosis in conjunction with natural history data can enable a long-term brain-penetrant anti-inflammatory regimen to optimise neurodevelopmental outcomes in genetic autoinflammatory brain disorders. Expedited genomic testing identified compound heterozygous ADAR1 mutations. Published natural history data from 33 patients with biallelic ADAR1 mutations reported severe disability (GMFCS V) or death in 79%. To reduce neuroinflammation, we commenced a long-term pulsed oral dexamethasone protocol (20 mg/m2 for 3 days every 3 weeks) from the age of 11 months, plus ruxolitinib, a Janus Kinase (JAK) inhibitor (5 mg per day). At the age of 24 months, the patient was crawling and walking a few steps unaided, with a GMFCS level of II. Single-cell RNA sequencing of 41 164 leukocytes, taken before and after 3 months of treatment and compared to three age matched male controls, showed a reversal of upregulated pan-cellular interferon pathways, with most differentially expressed genes observed in monocytes. On treatment, there was statistically significant downregulation of key autoinflammatory genes, including nucleic acid sensing (CGAS, IFIH1, SAMHD1), interferon-stimulated genes (ISG15 and IFIF44L) and signalling (JAK1). Given the dual immune therapy, it was not possible to define whether the biological effect was related to dexamethasone or JAK inhibitor, or both. Compared with natural history data, our data suggest that early diagnosis, and the use of early brain-penetrant immune suppressants (dexamethasone), may improve outcomes in ADAR1 AGS.
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Drug Discovery Landscape
3 orphan drug designations for Aicardi-Goutières syndrome.
3 orphan drug designations for Aicardi-Goutières syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
non-covalent competitive cGAS inhibitor | small molecules | FDA | 2024-09-25 | — | ImmuneSensor Therapeutics |
Emtricitabine | small molecules | EMA | 2015-01-15 | — | Dr Yanick Crow |
Tenofovir disoproxil fumarate | small molecules | EMA | 2015-01-15 | — | Dr Yanick Crow |
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