DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for aceruloplasminemia — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleAceruloplasminemia maps to a 1-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 aceruloplasminemia 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
ceruloplasmin (CP) — CP 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 oxydrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4ENZ · 2.6 Å · ligand OXYGEN MOLECULE (OXY). Experimental structure, not a prediction.
What the evidence adds up to
Aceruloplasminemia is an inherited neurodegenerative disease caused by loss-of-function mutations in the ceruloplasmin gene, leading to parenchymal iron accumulation. A 2002 study using Chinese hamster ovary cells transfected with the P177R missense mutant found that both the secreted and glycosylphosphatidylinositol-linked forms of the mutant ceruloplasmin are retained in the endoplasmic reticulum as an apoprotein; copper incorporation into ceruloplasmin occurs late in the secretory pathway. The P177R mutation lies within a novel motif repeated six times in human ceruloplasmin and conserved in hephaestin and factor VIII, and substitution of the arginine residue is critical for endoplasmic reticulum retention. A 2007 report identified a previously unknown compound heterozygosity in the ceruloplasmin gene of a 31-year-old man with iron overload, consisting of nucleotide replacements G229C and C2131A in exons 2 and 12, resulting in amino acid changes Asp58His and Gln692Lys. In silico analysis suggested Asp58His may interfere with copper incorporation or trafficking, and Gln692Lys may alter the cupredoxin fold conformation.
A 2011 histopathologic study of the aceruloplasminemic retina found retinal pigment epithelium depigmentation, atrophy and hypertrophy, nodular and diffuse drusen, and lipofuscin and melanolipofuscin granules, with complement deposition detected in drusen. Retinal pigment epithelium cells and neural retina had increased iron levels. Two major types of retinal pigment epithelium cells were observed: melanosome-rich cells with increased iron and melanolipofuscin, and melanosome-poor cells lacking melanosomes, melanolipofuscin, and lipofuscin but containing electron-dense aggregates high in iron, phosphorus, and sulphur. The findings resembled some features of age-related macular degeneration, and the authors suggested melanosomes in the retinal pigment epithelium may be degraded via iron-mediated reactive oxygen species production.
No treatment or intervention was tested in any of these studies. The 2007 report noted that 45 families with aceruloplasminemia had been reported worldwide at that time, but no clinical trial data, survival statistics, or response rates are available from these abstracts. What remains missing is any clinical trial testing iron chelation or other therapies, adequate patient stratification by genotype and disease stage, and funding for longitudinal natural history studies that could inform trial design.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Journal of Biological Chemistry · 2002 · 85 citations · open access
Biochemical Analysis of a Missense Mutation in Aceruloplasminemia
AbstractAceruloplasminemia is an inherited neurodegenerative disease characterized by parenchymal iron accumulation secondary to loss-of-function mutations in the ceruloplasmin gene. To elucidate the molecular pathogenesis of aceruloplasminemia, the biosynthesis of a missense mutant ceruloplasmin (P177R) occurring in an affected patient was examined. Chinese hamster ovary cells transfected with cDNAs encoding secreted and glycosylphosphatidylinositol (GPI)-linked wild-type or P177R human ceruloplasmin were examined by pulse-chase metabolic labeling. These experiments, as well as immunofluorescent analysis and N-linked glycosylation studies, indicate that both the secreted and GPI-linked forms of the P177R mutant are retained in the endoplasmic reticulum (ER). The P177R mutation resides within a novel motif, which is repeated six times in human ceruloplasmin and is conserved in the homologous proteins hephaestin and factor VIII. Analysis of additional mutations in these motifs suggests a critical role for this region in ceruloplasmin trafficking and indicates that substitution of the arginine residue is critical to the ER retention of the P177R mutant. Metabolic labeling of transfected Chinese hamster ovary cells with (64)Cu indicates that the P177R mutant is retained in the ER as an apoprotein and that copper is incorporated into both secreted and GPI-linked ceruloplasmin as a late event in the secretory pathway. Taken together, these studies reveal new insights into the determinants of holoceruloplasmin biosynthesis and indicate that aceruloplasminemia can result from retention of mutant ceruloplasmin within the early secretory pathway.
AbstractOBJECTIVE: To examine the retinal histopathologic manifestation of aceruloplasminemia, an autosomal recessive disease caused by mutation of the ferroxidase ceruloplasmin, resulting in tissue iron overload. METHODS: The morphologic features of the human aceruloplasminemic retina were studied with light and electron microscopy. Retinal iron accumulation was assessed with Perls Prussian blue staining, immunohistochemistry, and secondary ion mass spectrometry. RESULTS: Light and electron microscopic analysis revealed several ocular pathologic findings that resembled age-related macular degeneration, including retinal pigment epithelium (RPE) depigmentation, atrophy and hypertrophy, nodular and diffuse drusen, and lipofuscin and melanolipofuscin granules. Complement deposition was detected in drusen. The RPE cells and neural retina had increased levels of iron. Two major types of RPE cells were observed: melanosome rich and melanosome poor. Melanosome-rich cells had increased levels of iron and melanolipofuscin. The melanolipofuscin granules were observed in large aggregates, where some of the melanosomes were degrading. Melanosome-poor cells lacked melanosomes, melanolipofuscin, and lipofuscin but contained electron-dense aggregates high in iron, phosphorus, and sulfur. CONCLUSIONS: The findings in the aceruloplasminemic retina resemble some of those found in age-related macular degeneration. Also, they suggest that melanosomes in the RPE can be degraded via iron-mediated reactive oxygen species production. CLINICAL RELEVANCE: Mechanisms underlying the pathologic mechanisms found in aceruloplasminemia also may be important in age-related macular degeneration.
Scandinavian Journal of Gastroenterology · 2007 · 13 citations
Identification and<i>in silico</i>characterization of a novel compound heterozygosity associated with hereditary aceruloplasminemia
AbstractBACKGROUND: Hereditary aceruloplasminemia is an adult-onset autosomal recessive disease characterized by increased iron overload in the liver, pancreas, retina, and central nervous system. So far, 45 families with cases of aceruloplasminemia have been reported world-wide and mainly missense and nonsense mutations in the ceruloplasmin gene were detected. MATERIAL AND METHODS: Here, we report the identification, clinical characterization, and in silico analysis of a novel compound heterozygosity in the ceruloplasmin gene of a 31-year-old man with iron overload. RESULTS: Increased serum ferritin levels, elevated iron saturation, as well as results of iron quantification in the liver and magnetic resonance imaging-based measurement of T2 relaxation times of the substantia nigra consistently suggested iron overload. By sequencing the ceruloplasmin gene, so far unknown nucleotide replacements G229C, and C2131A were detected in exons 2 and 12, respectively. In silico analyses showed that the resulting amino acid changes Asp58His and Gln692Lys are located at highly conserved positions. The Asp58His mutation is located on the surface of the protein, alters polarity, and may interfere with copper incorporation or ceruloplasmin trafficking. The Gln692Lys mutation is mapped to a beta-strand of domain 4 and may lead to conformational change of the cupredoxin fold. CONCLUSIONS: As causative for aceruloplasminemia, a formerly unknown compound heterozygosity in the ceruloplasmin gene was identified. In silico characterization suggests an impact on ceruloplasmin conformation and function.
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.
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