DeCure for Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss
DeCure's autonomous Nephrology AI scientist is researching a drug-repurposing hypothesis for macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss — screening already-approved drugs against its 3-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleMacrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss maps to a 3-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 macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss 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
myosin heavy chain 9 (MYH9) — MYH9 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 adpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9SYU · 2.98 Å · ligand ADENOSINE-5'-DIPHOSPHATE (ADP). Experimental structure, not a prediction.
What the evidence adds up to
In a 2017 study of two unrelated families with autosomal-dominant sensorineural hearing loss caused by NLRP3 mutation, one family (LMG446) showed hearing loss accompanied by autoinflammatory signs without serologic evidence of inflammation, as part of an atypical CAPS phenotype. In that family, hearing loss was reversed or improved by IL-1β blockade with anakinra. The other family (LMG113) had hearing loss without any other CAPS target-organ manifestations. The authors demonstrated that the NLRP3 inflammasome can be activated in resident macrophage-like cells in the mouse cochlea, leading to secretion of IL-1β. They proposed this pathway could underlie treatable hearing loss in DFNA34, CAPS, and possibly in sudden sensorineural hearing loss and Meniere’s disease.
A 2020 case report described a gain-of-function mutation in DIAPH1 as a novel cause of autosomal dominant macrothrombocytopenia and sensorineural hearing loss. The mutation caused altered megakaryopoiesis and platelet cytoskeletal deregulation. Clinically significant bleeding was not observed, though hearing loss and macrothrombocytopenia were likely progressive. The authors noted that DIAPH1-related disease can be distinguished from MYH9 mutation by the absence of cataracts and glomerular disease.
A 2012 report on two cases of granulomatosis with polyangiitis (formerly Wegener’s granulomatosis) presenting with both conductive and sensorineural hearing loss without systemic features found that early recognition and treatment reversed hearing loss and prevented disease progression. In contrast, delayed diagnosis led to persistent deafness and systemic disease requiring more aggressive therapy. The authors stressed that a negative or weak ANCA with absent antibodies to proteinase 3 and myeloperoxidase should not exclude the diagnosis.
No abstract directly addresses the full combination of macrothrombocytopenia, granulocyte inclusions, nephritis, and sensorineural hearing loss. The NLRP3 and DIAPH1 studies each cover only hearing loss with either autoinflammation or macrothrombocytopenia, not the complete syndromic picture. The GPA report involves hearing loss and renal disease but not thrombocytopenia or granulocyte inclusions. What is missing is a trial or case series testing anakinra or any other drug in patients who have the full triad of macrothrombocytopenia, granulocyte inclusions, and hearing loss with or without nephritis. No study has stratified patients by genetic diagnosis or measured bleeding outcomes under treatment. Funding for such a stratified trial and a reliable diagnostic pathway for these rare overlapping syndromes are lacking.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Proceedings of the National Academy of Sciences · 2017 · 152 citations · open access
<i>NLRP3</i> mutation and cochlear autoinflammation cause syndromic and nonsyndromic hearing loss DFNA34 responsive to anakinra therapy
Abstractcauses autosomal-dominant sensorineural hearing loss in two unrelated families. In family LMG446, hearing loss is accompanied by autoinflammatory signs and symptoms without serologic evidence of inflammation as part of an atypical CAPS phenotype and was reversed or improved by IL-1β blockade therapy. In family LMG113, hearing loss segregates without any other target-organ manifestations of CAPS. This observation led us to explore the possibility that resident macrophage/monocyte-like cells in the cochlea can mediate local autoinflammation via activation of the NLRP3 inflammasome. The NLRP3 inflammasome can indeed be activated in resident macrophage/monocyte-like cells in the mouse cochlea, resulting in secretion of IL-1β. This pathway could underlie treatable sensorineural hearing loss in DFNA34, CAPS, and possibly in a wide variety of hearing-loss disorders, such as sudden sensorineural hearing loss and Meniere's disease that are elicited by pathogens and processes that stimulate innate immune responses within the cochlea.
<b><i>DIAPH1</i></b> Mutation as a Novel Cause of Autosomal Dominant Macrothrombocytopenia and Hearing Loss
AbstractMacrothrombocytopenia (MTP) is a group of rare disorders characterized by giant platelets, thrombocytopenia, and variable association with abnormal bleeding. Inherited MTP are frequently misdiagnosed as immune thrombocytopenia. Associated second-organ manifestation can help narrow down syndromic MTPs. We describe a case of autosomal dominant sensorineural hearing loss and MTP caused by a gain of function mutation in DIAPH1. This mutation causes altered megarkaryopoiesis and platelet cytoskeletal deregulation. Although hearing loss and MTP were likely progressive, clinically significant bleeding was not observed. DIAPH1-related MTP can be distinguished clinically from MYH9 mutation by the absence of cataracts and glomerular disease.
American Journal of Audiology · 2012 · 11 citations
Early Intervention in Localized Wegener’s Granulomatosis With Sensorineural Hearing Loss Preserves Hearing
AbstractPURPOSE: Wegener's granulomatosis has been renamed granulomatosis with polyangiitis (GPA). In this article, the authors refer to WG as "WG/GPA" to indicate the old and new names of this condition. WG/GPA is a systemic necrotizing granulomatous vasculitis that can affect, in particular, the lungs, sinuses, and kidneys. The authors report 2 cases with antineutrophil cytoplasmic antibodies (c-ANCA) positive WG/GPA whose initial presentations were in the form of both conductive and sensorineural hearing loss without systemic features. The authors contrast the reversal of hearing loss and prevention of disease progression with early recognition and treatment. METHOD: The authors present 2 contrasting cases of WG/GPA. Changes in hearing were measured through use of a GSI 61 audiometer as well as guidelines from the British Society of Audiology. Serum ANCA were detected by indirect immunofluorescence and formalin fixed neutrophils. Proteinase 3 (PR3) and myeloperoxidase antibodies were measured through use of a fluoroenzyme immunoassay. RESULTS: Persistent deafness and systemic disease are more likely, and more aggressive therapy was required when the diagnosis of WG/GPA was delayed. CONCLUSION: WG/GPA should be considered in acute or subacute deafness presenting over days to weeks and even in the absence of systemic symptoms. A negative or weak ANCA with absent antibodies to serine PR3 and myeloperoxidase should not exclude the possible diagnosis of WG/GPA, and a high index of suspicion should be maintained.
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.
