DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for ciliopathy — screening already-approved drugs against its 35-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleCiliopathy maps to a 35-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
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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 ciliopathy 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
nuclear receptor subfamily 1 group H member 4 (NR1H4) — NR1H4 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 iiidrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3BEJ · 1.9 Å · ligand YTTRIUM (III) ION (YT3). Experimental structure, not a prediction.
What the evidence adds up to
Ciliopathies are a class of genetic multisystemic disorders unified by shared clinical features such as mental retardation, cystic kidney, retinal defects and polydactyly, and by the common localisation of protein products at or near the primary cilium. They are mostly inherited as simple recessive traits, but phenotypic expressivity is under the control of numerous genetic modifiers. A 2013 review notes that a database survey searching for combinations of ciliopathy-associated features identified 193 congenital disorders, only a minority of which were confirmed ciliopathies. Next generation sequencing is rapidly identifying the genetic causality of many of these rare syndromes, but a proportion remain unresolved, and many mechanisms are incompletely understood.
A 2020 case report describes a 15-year-old girl with Senior-Løken syndrome associated with compound heterozygous mutations in the SDCCAG8 gene. She initially presented with retinal dystrophy and subsequent renal failure requiring renal transplantation and immunosuppression. Four and a half years later, she presented with headaches, reduced vision and papilloedema. Cerebrospinal fluid analysis revealed a high opening pressure of 37 cmH2O. Treatment with a reduced dose of oral acetazolamide resulted in symptomatic relief of headaches and resolution of optic nerve swelling. The authors state that the aetiology of intracranial hypertension in this case is likely multi-factorial, due to renal transplantation, post-renal transplant medications and/or weight gain, and that ciliary dysfunction may contribute.
A 2023 retrospective case series of three children with RPGR-related rod-cone dystrophy, all with mutations in the N-terminus of RPGR, reports that two cases co-presented with confirmed diagnoses of primary ciliary dyskinesia and one case with multiple sino-respiratory symptoms strongly suggestive of primary ciliary dyskinesia. The authors conclude that the link between RPGR variants and a systemic ciliopathy remains plausible but currently unproven. No other systemic associations were found in these or all previously reported RPGR co-pathologies.
What is still missing is a comprehensive understanding of all genes required for ciliogenesis, how the encoded proteins work together in complexes and networks, and the signalling pathways and modifier relationships involved. For many syndromes, a diagnosis that can fully account for clinical features, provide accurate guidance on recurrence risk and prognosis, and facilitate targeted management and support remains an ongoing process. No clinical trials of any drug for ciliopathy are reported in these abstracts.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Genome Medicine · 2011 · 94 citations · open access
A systems-biology approach to understanding the ciliopathy disorders
Abstract'Ciliopathies' are an emerging class of genetic multisystemic human disorders that are caused by a multitude of largely unrelated genes that affect ciliary structure/function. They are unified by shared clinical features, such as mental retardation, cystic kidney, retinal defects and polydactyly, and by the common localization of the protein products of these genes at or near the primary cilium of cells. With the realization that many previously disparate conditions are a part of this spectrum of disorders, there has been tremendous interest in the function of cilia in developmental signaling and homeostasis. Ciliopathies are mostly inherited as simple recessive traits, but phenotypic expressivity is under the control of numerous genetic modifiers, putting these conditions at the interface of simple and complex genetics. In this review, we discuss the ever-expanding ciliopathy field, which has three interrelated goals: developing a comprehensive understanding of genes mutated in the ciliopathies and required for ciliogenesis; understanding how the encoded proteins work together in complexes and networks to modulate activity and structure-function relationships; and uncovering signaling pathways and modifier relationships.
Senior-Løken syndrome and intracranial hypertension
AbstractBackground Senior-Løken syndrome (SLS) is a rare autosomal recessive disease characterised by nephronophthisis and retinal degeneration, and belongs to a group of genetically heterogeneous disorders known as the ciliopathies.Materials and Methods Case report of a patient with genetically proven SLS presenting with headaches and swollen optic nerve heads, review of medical notes and ophthalmic imaging, with retinal photography, fundus autofluorescence, and OCT retinal nerve fibre layer analysis.Results We present findings in a 15 year old girl with Senior-Løken syndrome associated with compound heterozygous mutations in the SDCCAG8 gene, who initially presented with a retinal dystrophy, and subsequent renal failure requiring renal transplantation and immunosuppression. Four and a half years later, she presented with headaches, reduced vision and clinical findings of papilloedema. Cerebrospinal fluid analysis revealed a high opening pressure of 37cmH20 and neuroimaging was otherwise unremarkable. Treatment with a reduced dose of oral acetazolamide resulted in symptomatic relief of headaches, and resolution of optic nerve swelling.Conclusion The association of intracranial hypertension in a ciliopathy is a rare occurrence. The aetiology of intracranial hypertension in this case is likely multi-factorial, due to renal transplantation, post-renal transplant medications and/ or weight gain. With evidence of cilia involvement in the central nervous system, ciliary dysfunction may contribute to intracranial hypertension, and should be considered in these patients presenting with headaches. Diagnosis may be difficult with advanced retinal degeneration and baseline retinal nerve fibre layer thinning. Treatment requires careful monitoring of renal function.
Is RPGR-related retinal dystrophy associated with systemic disease? A case series
AbstractBACKGROUND: Ciliopathies responsible for retinitis pigmentosa can also cause systemic manifestations. RPGR is a ciliary gene and pathogenic variants in RPGR cause a retinal ciliopathy, the commonest cause of X-linked recessive retinitis pigmentosa. The RPGR protein interacts with numerous other ciliary proteins present in the transition zone of both motile and sensory cilia, and may play an important role in regulating ciliary protein transport. There has been a growing, putative association of RPGR variants with systemic ciliopathies: mainly sino-respiratory infections and primary ciliary dyskinesia. MATERIALS AND METHODS: Retrospective case series of patients with RPGR-RP presenting to Oxford Eye Hospital with systemic disease. RESULTS: We report three children with RPGR-related rod-cone dystrophy, all of whom have mutations in the N-terminus of RPGR. Two cases co-presented with confirmed diagnoses of primary ciliary dyskinesia and one case with multiple sino-respiratory symptoms strongly suggestive of primary ciliary dyskinesia. These and all previously reported RPGR co-pathologies relate to ciliopathies and have no other systemic associations. CONCLUSIONS: The link between RPGR variants and a systemic ciliopathy remains plausible, but currently unproven.
Oxford University Press eBooks · 2013 · 0 citations
Syndromes not yet proven to be ciliopathies
AbstractSyndromes not yet proven to be ciliopathies are large in number and diverse in clinical presentations. A previous database survey, searching for combinations of ciliopathy-associated features, identified 193 congenital disorders, only a minority of which were confirmed ciliopathies. This chapter will review progress in resolving the remaining suspected ciliopathies. Next Generation sequencing is rapidly identifying the genetic causality of many of these rare syndromes, and functional studies of patient-derived tissues or animal models are providing follow-on evidence for ciliary dysfunction. Genomic mechanisms such as oligogenic inheritance, mutational load and somatic mosaicism are emerging as important themes. A proportion of syndromes remain unresolved, and many mechanisms are incompletely understood. For patients and families, this entails an on-going process of obtaining a diagnosis that can fully account for clinical features, can provide accurate guidance on recurrence risk and prognosis, and can facilitate targeted management and support.
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.
