DeCure for TNF receptor 1-associated periodic fever syndrome
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for TNF receptor 1-associated periodic fever syndrome — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleTNF receptor 1-associated periodic fever syndrome maps to a 2-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for tnf receptor 1-associated periodic fever syndrome is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
TNF receptor superfamily member 1A (TNFRSF1A) — TNFRSF1A is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8ZUI · 2.56 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
TNF receptor 1-associated periodic syndrome (TRAPS) is an autosomal dominant autoinflammatory disorder caused by mutations in the TNFRSF1A gene. It appears to be the most common hereditary periodic fever syndrome in some Western populations and the second most prevalent worldwide behind familial Mediterranean fever. Most patients have reduced blood levels of soluble TNFRSF1A between attacks, with an inappropriately small increase during fever bouts. One study of a French family carrying the C30S mutation found that during attacks, soluble TNFR1 levels remained abnormally low compared to patients with active adult-onset systemic Still's disease. The same study reported that membrane TNFR1 expression on monocytes and polymorphonuclear leukocytes was not modified in mutation carriers when disease was not active.
Two Dutch patients with recurrent fever attacks went undiagnosed for more than 40 years before molecular analysis revealed novel TNFRSF1A mutations. One of these patients received a short course of recombinant p75TNFR:Fc fusion protein (etanercept) and achieved prolonged remission. A 58-year-old patient with the low-penetrance R92Q mutation responded well to anti-tumour necrosis factor α therapy. Synthetic anti-TNF agents have been shown to delay or prevent development of systemic amyloidosis (AA type), a life-threatening complication. However, laboratory studies using transfected cell lines indicate that TRAPS-associated variants of TNFR1 enhance cytokine production through both TNF-dependent and TNF-independent mechanisms. In SK-HEP-1 cells, specific TRAPS mutations increased the cytokine response to TNF compared to wild-type, and this augmented production was suppressed by an anti-TNFR1 single domain antibody. The TNF-independent mechanism was not inhibited by that antibody in cells transfected with death domain-inactivated TNFR1.
The IL-1 receptor antagonist anakinra has been reported as an efficacious daily treatment. Interim clinical and pharmacokinetic data from canakinumab treatment in patients with active TRAPS were presented in 2013 but no efficacy results are given in the available abstract. Some low-penetrance TNFRSF1A variants also contribute to the clinical phenotype in individuals carrying other hereditary periodic fever mutations and have been reported in Behçet's disease and systemic lupus erythematosus. The C30S mutation in the first extracellular cysteine-rich domain of TNFR1 was identified in a French family where the propositus had MRI evidence of abnormal signals in muscle and subcutaneous tissue without involvement of adjacent joints or fascia.
What remains missing are large controlled trials comparing anti-TNF agents, anti-IL-1 agents, and no treatment in genetically confirmed TRAPS patients, with standardised outcome measures for attack frequency, severity, and amyloidosis prevention. The rarity of the condition makes recruitment difficult, and the heterogeneity of mutations and penetrance complicates patient stratification.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Expert Reviews in Molecular Medicine · 2005 · 86 citations
the tumour necrosis factor receptor-associated periodic syndrome: current concepts
AbstractThe tumour necrosis factor receptor (TNFR)-associated periodic syndrome (TRAPS) is an autosomal dominant, multisystemic, autoinflammatory disorder caused by mutations in the TNFR1 gene ( TNFRSF1A ). Traps seems to be the most common hereditary periodic fever (HPF) syndrome in some western populations, and the second most prevalent HPF worldwide, behind familial mediterranean fever (FMF). The proteins involved in susceptibility to TRAPS (TNFRSF1A) and FMF (pyrin) are both members of the death-domain-fold superfamily. Mutations affecting these proteins might cause dysregulation of innate immune responses, with a propensity to autoinflammation. Most TRAPS patients have reduced blood levels of soluble TNFRSF1A between attacks, with an inappropriately small increase during bouts of fever. The pathogenesis of the 'hyperinflammatory state' in TRAPS has been variously ascribed to a shedding defect of TNFRSF1A from the cell surface resulting in increased TNF inflammatory signalling, or impaired TNF apoptotic signalling. Some low-penetrance TNFRSF1A variants also contribute to the clinical phenotype in individuals carrying other HPF-associated mutations, and have been reported in several disorders such as Behçet's disease and systemic lupus erythematosus. Synthetic anti-TNF agents provide a rational form of therapy for TRAPS, and have been shown to delay or indeed prevent development of systemic amyloidosis (AA type), a life-threatening complication in this condition.
Archives of Internal Medicine · 2001 · 33 citations
Genetic Analysis as a Valuable Key to Diagnosis and Treatment of Periodic Fever
AbstractWe describe 2 Dutch patients with recurrent fever attacks undiagnosed for more than 40 years. The diagnosis of periodic fever was made when molecular analysis revealed novel mutations in the tumor necrosis factor (TNF) receptor gene (TNFRSF1A), establishing the diagnosis of TNF receptor-associated periodic syndrome. This syndrome is an autosomal dominant disorder characterized by recurring episodes of fever, arthralgia, and skin lesions that is caused by mutations in the 55-kd TNFRSF1A gene. This finding has facilitated treatment for TNF receptor-associated periodic syndrome because blocking of TNF signaling seems to alleviate the symptoms. Use of a short course of recombinant p75TNFR:Fc fusion protein (etanercept) induced prolonged remission in one patient.
European Journal of Immunology · 2015 · 10 citations · open access
Tumour necrosis factor receptor I blockade shows that TNF‐dependent and TNF‐independent mechanisms synergise in TNF receptor associated periodic syndrome
AbstractTNF receptor associated periodic syndrome (TRAPS) is an autoinflammatory disease involving recurrent episodes of fever and inflammation. It is associated with autosomal dominant mutations in TNF receptor superfamily 1A gene localised to exons encoding the ectodomain of the p55 TNF receptor, TNF receptor-1 (TNFR1). The aim of this study was to investigate the role of cell surface TNFR1 in TRAPS, and the contribution of TNF-dependent and TNF-independent mechanisms to the production of cytokines. HEK-293 and SK-HEP-1 cell lines were stably transfected with WT or TRAPS-associated variants of human TNF receptor superfamily 1A gene. An anti-TNFR1 single domain antibody (dAb), and an anti-TNFR1 mAb, bound to cell surface WT and variant TNFR1s. In HEK-293 cells transfected with death domain-inactivated (R347A) TNFR1, and in SK-HEP-1 cells transfected with normal (full-length) TNFR1, cytokine production stimulated in the absence of exogenous TNF by the presence of certain TNFR1 variants was not inhibited by the anti-TNFR1 dAb. In SK-Hep-1 cells, specific TRAPS mutations increased the level of cytokine response to TNF, compared to WT, and this augmented cytokine production was suppressed by the anti-TNFR1 dAb. Thus, TRAPS-associated variants of TNFR1 enhance cytokine production by a TNF-independent mechanism and by sensitising cells to a TNF-dependent stimulation. The TNF-dependent mechanism requires cell surface expression of TNFR1, as this is blocked by TNFR1-specific dAb.
JCR Journal of Clinical Rheumatology · 2011 · 6 citations
Tumor Necrosis Factor Receptor-Associated Periodic Fever Syndrome in a 58-Year-Old Man
AbstractTumor necrosis factor receptor-associated periodic fever syndrome (TRAPS) is a rare systemic autoinflammatory disorder characterized by recurrent episodes of fever and localized inflammation of different organs. The disease is dominantly inherited, with an onset usually in early childhood. We describe a case of a 58-year-old patient with TRAPS caused by the low-penetrance R92Q mutation in TNFRSF1A gene. The patient responded well to anti-tumor necrosis factor α therapy. Although periodic fever syndromes, including TRAPS, mainly begin in early childhood, it is important to consider periodic fever syndrome also in patient presenting at an age older than the average reported case for TRAPS.
Pediatric Rheumatology · 2013 · 2 citations · open access
OR10-006 - Canakinumab in patients with TRAPS
AbstractTNF-receptor associated periodic syndrome (TRAPS) is a rare, dominantly inherited periodic fever syndrome due to mutations of the TNFRSF1A gene. The IL-1 receptor antagonist anakinra has been reported to be an efficacious daily treatment. Canakinumab (CAN) is a fully human monoclonal selective anti-IL-1β antibody with a T 1/2 of ~4 wks. Interim clinical and PK data of CAN treatment in patients with active TRAPS are presented.
A novel missense mutation (C30S) in the gene encoding tumor necrosis factor receptor 1 linked to autosomal-dominant recurrent fever with localized myositis in a French family
AbstractObjective To characterize both phenotypic (clinical features and magnetic resonance imaging [MRI] findings) and genotypic aspects of autosomal-dominant recurrent fever, also known as tumor necrosis factor receptor (TNFR)–associated periodic syndrome (TRAPS), in a French family and to investigate the role of the mutated 55-kd tumor necrosis factor α (TNFα) receptor (TNFR1) in the pathogenesis of the disease. Methods The coding region of TNFR1 was sequenced in 2 individuals with TRAPS (the propositus and her grandfather) and in 3 clinically unaffected relatives. Expression of soluble TNFR1 (sTNFR1) was investigated in 3 of the family members carrying a C30S mutation in TNFR1, and was compared with the levels of soluble TNFR2 (sTNFR2) by enzyme-linked immunosorbent assay. The membrane TNFR1 expression was then compared with membrane TNFR2 levels at the surface of peripheral blood mononuclear cells by flow cytometric analysis. The clinical heterogeneity in this French family was investigated by searching polymorphic variants in the TNFα promoter by DNA sequencing. Results Both the disease course and the clinical presentation in the propositus were highly indicative of TRAPS. MRI study of the segmental inflammatory process in the limbs showed abnormal signals in the muscle and subcutaneous tissue without involvement of adjacent joints or fascia. A novel missense mutation, C30S, in the first extracellular N-terminal cysteine-rich domain (CRD1) of TNFR1 was characterized in the propositus, her affected grandfather, and her clinically unaffected father. Expression of membrane TNFR1 at the surface of monocytes and polymorphonuclear leukocytes, as well as the levels of sTNFR1 in serum when the disease was not active were not modified in the 3 individuals carrying the TNFR1 C30S mutation. In contrast, during attacks, sTNFR1 levels remained abnormally low, as compared with the levels in unrelated patients with active adult-onset systemic Still's disease. The clinical heterogeneity could not be explained by a polymorphic variant in the TNFα promoter. Conclusion TRAPS is a distinct clinical and radiologic disease entity that is responsible for recurrent fever and migratory cellulitis-like processes with localized myositis. We have identified a novel TNFR1 mutation, C30S, that is located in the CRD1 domain in a French family affected by the disease. This mutation seems to affect the level of sTNFR1, which did not increase in the propositus during inflammatory attacks.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
