Reverse-Transcriptase Inhibitors in the Aicardi–Goutières Syndrome

Rice, Gillian I.; Meyzer, Candice; Bouazza, Naïm; Hully, Marie; Boddaert, Nathalie; Semeraro, Michaela; Zeef, Leo; Rozenberg, Flore; Bondet, Vincent; Duffy, Darragh; Llibre, Alba; Baek, Jinmi; Sambe, Mame N; Henry, Elodie; Jolaine, Valérie; Barnérias, Christine; Barth, Magalie; Belot, Alexandre; Cancés, Claude; Debray, François-Guillaume; Doummar, Diane; Frémond, Marie-Louise; Kitabayashi, Naoki; Lepelley, Alice; Levrat, Virginie; Melki, Isabelle; Meyer, Pierre; Nouguès, Marie‐Christine; Renaldo, Florence; Rodero, Mathieu P; Rodriguez, Diana; Roubertie, Agathe; Seabra, Luis; Uggenti, Carolina; Abdoul, Hendy; Tréluyer, Jean‐Marc; Desguerre, Isabelle; Blanche, Stéphane; Crow, Yanick J.

doi:10.1056/nejmc1810983

Cited by 114 publications

(97 citation statements)

References 4 publications

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“…LINE‐1 loci are also transcriptionally active in patients with Aicardi‐Goutières syndrome , suggesting that LINE‐1 ORF2p is indeed the reverse transcriptase responsible for the aberrant DNA that drives type I IFN production and the disease in patients with Aicardi‐Goutières syndrome . Inhibitors of the reverse transcriptase can reduce the IFN gene signature in patients with Aicardi‐Goutières syndrome .…”

Section: Introductionmentioning

confidence: 99%

High Prevalence and Disease Correlation of Autoantibodies Against p40 Encoded by Long Interspersed Nuclear Elements in Systemic Lupus Erythematosus

Carter

LaCava

Taylor

et al. 2019

Arthritis & Rheumatology

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Objective Long interspersed nuclear element 1 (LINE‐1) encodes 2 proteins, the RNA binding protein p40 and endonuclease and reverse transcriptase (open‐reading frame 2p [ORF2p]), which are both required for LINE‐1 to retrotranspose. In cells expressing LINE‐1, these proteins assemble with LINE‐1 RNA and additional RNA binding proteins, some of which are well‐known autoantigens in patients with systemic lupus erythematosus (SLE). This study was undertaken to investigate whether SLE patients also produce autoantibodies against LINE‐1 p40. Methods Highly purified p40 protein was used to quantitate IgG autoantibodies in serum from 172 SLE patients and from disease controls and age‐matched healthy subjects by immunoblotting and enzyme‐linked immunosorbent assay (ELISA). Preparations of p40 that also contained associated proteins were analyzed by immunoblotting with patient sera. Results Antibodies reactive with p40 were detected in the majority of patients and many healthy controls. Their levels were higher in patients with SLE, but not those with systemic sclerosis, compared to healthy subjects (P = 0.01). Anti‐p40 reactivity was higher in patients during a flare than in patients with disease in remission (P = 0.03); correlated with the SLE Disease Activity Index score (P = 0.0002), type I interferon score (P = 0.006), decrease in complement C3 level (P = 0.0001), the presence of anti‐DNA antibodies (P < 0.0001) and anti‐C1q antibodies (P = 0.004), and current or past history of nephritis (P = 0.02 and P = 0.003, respectively); and correlated inversely with age (r = −0.49, P < 0.0001). SLE patient sera also reacted with p40‐associated proteins. Conclusion Autoantibodies reacting with LINE‐1 p40 characterize a population of SLE patients with severe and active disease. These autoantibodies may represent an early immune response against LINE‐1 p40 that does not yet by itself imply clinically significant autoimmunity, but may represent an early, and still reversible, step toward SLE pathogenesis.

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Section: Introductionmentioning

confidence: 99%

High Prevalence and Disease Correlation of Autoantibodies Against p40 Encoded by Long Interspersed Nuclear Elements in Systemic Lupus Erythematosus

Carter

LaCava

Taylor

et al. 2019

Arthritis & Rheumatology

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“…[16][17][18][19] Additionally, patients with mutations in the RNASE H2 complex in particular exhibited reductions in interferon signaling following treatment with a combination of anti-human immunodeficiency virus-1 reverse transcriptase inhibitors (abacavir, lamivudine, and zidovudine). 20 "Broad-spectrum" immunosuppression (for example, plasmapheresis, corticosteroid, IV Ig, and mycophenolate mofetil therapy as trialed in this case) has failed to demonstrate notable improvement in isolated case reports of AGS. 8,18,21 This case highlights the clinical and radiological heterogeneity of AGS, a condition that is likely under-recognized and therefore underdiagnosed.…”

Section: Discussionmentioning

confidence: 85%

“…Therapies to block interferon signaling may therefore be of utility in patients exhibiting recurrent symptomatology, and several Janus kinase inhibitors have shown early promise in several type I interferonopathies . Additionally, patients with mutations in the RNASE H2 complex in particular exhibited reductions in interferon signaling following treatment with a combination of anti‐human immunodeficiency virus‐1 reverse transcriptase inhibitors (abacavir, lamivudine, and zidovudine) . “Broad‐spectrum” immunosuppression (for example, plasmapheresis, corticosteroid, IV Ig, and mycophenolate mofetil therapy as trialed in this case) has failed to demonstrate notable improvement in isolated case reports of AGS …”

Section: Discussionmentioning

confidence: 99%

Relapsing–remitting clinical course expands the phenotype of Aicardi–Goutières syndrome

Lambe

Murphy

et al. 2020

Ann Clin Transl Neurol

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Aicardi–Goutières syndrome (AGS) is a rare and likely underdiagnosed genetic leukoencephalopathy, typically presenting in infancy with encephalopathy and characteristic neuroimaging features, with residual static neurological deficits. We describe a patient who, following an initial presentation at the age of 12 months in keeping with AGS, exhibited a highly atypical relapsing course of neurological symptoms in adulthood with essentially normal neuroimaging. Whole‐exome sequencing confirmed a pathogenic RNASEH2B gene variant consistent with AGS. This case highlights the expanding phenotypes associated with AGS and the potential role of whole‐exome sequencing in facilitating an increase in the rate of diagnosis.

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“…These results were not reproduced by another group, and the reason for this discrepancy is unclear. However, based on the former study, and supported by in vitro data generated using induced pluripotent stem cell technology, the results of the first clinical trial of RTIs in AGS have recently been published . In an open‐label pilot study, patients with mutations in TREX1 , RNASEH2A , RNASEH2B, or SAMHD1 were treated with a combination of three anti‐human immunodeficiency virus‐1 RTIs (abacavir, lamivudine, and zidovudine) over a period of 12 months, with interferon status assessed before, during, and after treatment.…”

Section: Implications For Therapies Derived From Insights Into Pathogmentioning

confidence: 99%

Treatments in Aicardi–Goutières syndrome

Crow

Shetty

Livingston

2019

Develop Med Child Neuro

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AGSAicardi-Gouti eres syndrome RTI Reverse transcriptase inhibitor Comprehensive reviews of the clinical characteristics and pathogenesis of Aicardi-Gouti eres syndrome (AGS), particularly its contextualization within a putative type I interferonopathy framework, already exist. However, recent reports of attempts at treatment suggest that an assessment of the field from a therapeutic perspective is warranted at this time. Here, we briefly summarize the neurological phenotypes associated with mutations in the seven genes so far associated with AGS, rehearse current knowledge of the pathology as it relates to possible treatment approaches, critically appraise the potential utility of therapies, and discuss the challenges in assessing clinical efficacy.

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Reverse-Transcriptase Inhibitors in the Aicardi–Goutières Syndrome

Cited by 114 publications

References 4 publications

High Prevalence and Disease Correlation of Autoantibodies Against p40 Encoded by Long Interspersed Nuclear Elements in Systemic Lupus Erythematosus

High Prevalence and Disease Correlation of Autoantibodies Against p40 Encoded by Long Interspersed Nuclear Elements in Systemic Lupus Erythematosus

Relapsing–remitting clinical course expands the phenotype of Aicardi–Goutières syndrome

Treatments in Aicardi–Goutières syndrome

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