DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Enchondromatosis — screening already-approved drugs against its 5-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleEnchondromatosis maps to a 5-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 enchondromatosis 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
isocitrate dehydrogenase (NADP(+)) 2 (IDH2) — IDH2 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 ndpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 5I96 · 1.55 Å · ligand NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE (NDP). Experimental structure, not a prediction.
What the evidence adds up to
The PTHR1 gene has been investigated as a possible contributor to Ollier disease, but the evidence is contradictory. A 2008 study of 61 Ollier disease and 23 Maffucci syndrome patients found three new missense mutations in PTHR1 (p.G121E, p.A122T, p.R255H) that impaired receptor function by reducing either affinity for PTH or cell-surface expression. These mutations were absent from 222 controls. Including earlier data, functionally deleterious PTHR1 mutations had been identified in five out of 31 enchondromas from Ollier patients. However, a 2004 study of 31 enchondromatosis patients from three European countries could not confirm the previously reported p.R150C mutation in 26 tumours, nor find any other PTHR1 mutations in 11 patients screened by sequencing. That study also reported normal PTHR1 protein expression by immunohistochemistry. The 2008 authors acknowledged that the p.R150C mutation was absent in 26 tumours from another study, and that no other PTHR1 mutations were found in 11 patients from that same cohort.
More recent work has shifted attention to IDH mutations. A 2024 study used single-cell RNA sequencing of growth plates from E18.5 mice expressing a mutant Idh1 in Col2-expressing cells. Compared to control littermates, the mutant growth plates contained a unique cluster of cells expressing genes known to be upregulated in human enchondromas, and a separate cluster of cells important for longitudinal bone growth was underrepresented. Immunofluorescence showed the enchondroma-associated genes were expressed across multiple growth plate zones, and pseudo-time analysis suggested these cells could arise from several chondrocyte subpopulations. The authors concluded that a subpopulation of chondrocytes become enchondromas at the expense of contributing to longitudinal growth.
A 2012 review argued that the various enchondromatoses are heterogeneous at the molecular level, with some forms (Ollier disease, Maffucci syndrome, metaphyseal chondromatosis with hydroxyglutaric aciduria, metachondromatosis) involving dysregulation of chondrocyte proliferation, and others (spondyloenchondrodysplasia, dysspondyloenchondromatosis) caused by defects in cartilage or bone matrix structure or metabolism. The review noted that many cases remain difficult to diagnose and classify, implying more variants remain to be defined. A 1971 report of two cases followed over 20 years described a tendency toward spontaneous arrest and even regression of the disease with growth, and noted that X-ray findings at diagnosis varied from those considered characteristic of Ollier disease.
What is still missing is a consistent molecular target that applies to most patients, given the conflicting PTHR1 data and the fact that IDH mutations have been studied only in mice. No clinical trial has tested a drug in enchondromatosis patients based on these mechanisms. Patient stratification by genotype and natural history is lacking, and funding for such trials remains absent.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Human Molecular Genetics · 2008 · 128 citations · open access
PTHR1 mutations associated with Ollier disease result in receptor loss of function
AbstractPTHR1-signaling pathway is critical for the regulation of endochondral ossification. Thus, abnormalities in genes belonging to this pathway could potentially participate in the pathogenesis of Ollier disease/Maffucci syndrome, two developmental disorders defined by the presence of multiple enchondromas. In agreement, a functionally deleterious mutation in PTHR1 (p.R150C) was identified in enchondromas from two of six unrelated patients with enchondromatosis. However, neither the p.R150C mutation (26 tumors) nor any other mutation in the PTHR1 gene (11 patients) could be identified in another study. To further define the role of PTHR1-signaling pathway in Ollier disease and Maffucci syndrome, we analyzed the coding sequences of four genes (PTHR1, IHH, PTHrP and GNAS1) in leucocyte and/or tumor DNA from 61 and 23 patients affected with Ollier disease or Maffucci syndrome, respectively. We identified three previously undescribed missense mutations in PTHR1 in patients with Ollier disease at the heterozygous state. Two mutations (p.G121E, p.A122T) were present only in enchondromas, and one (p.R255H) in both enchondroma and leukocyte DNA. Assessment of receptor function demonstrated that these three mutations impair PTHR1 function by reducing either the affinity of the receptor for PTH or the receptor expression at the cell surface. These mutations were not found in DNA from 222 controls. Including our data, PTHR1 functionally deleterious mutations have now been identified in five out 31 enchondromas from Ollier patients. These findings provide further support for the idea that heterozygous mutations in PTHR1 that impair receptor function participate in the pathogenesis of Ollier disease in some patients.
Human Mutation · 2004 · 76 citations · open access
Enchondromatosis (Ollier disease, Maffucci syndrome) is not caused by the PTHR1 mutation p.R150C
AbstractEnchondromatosis (Ollier disease, Maffucci syndrome) is a rare developmental disorder characterized by multiple enchondromas. Not much is known about its molecular genetic background. Recently, an activating mutation in the parathyroid hormone receptor type 1 (PTHR1) gene, c.448C>T (p.R150C), was reported in two of six patients with enchondromatosis. The mutation is thought to result in upregulation of the IHH/PTHrP pathway. This is in contrast to previous studies, showing downregulation of this pathway in other cartilaginous tumors. Therefore, we investigated PTHR1 in enchondromas and chondrosarcomas from 31 enchondromatosis patients from three different European countries, thereby excluding a population bias. PTHR1 protein expression was studied using immunohistochemistry, revealing normal expression. The presence of the described PTHR1 mutation was analyzed, using allele-specific oligonucleotide hybridization confirmed by sequence analysis, in tumors from 26 patients. In addition, 11 patients were screened for other mutations in the PTHR1 gene by sequence analysis. Using both allele-specific oligonucleotide hybridization and sequencing, we could neither confirm the previously found mutation nor find any other mutations in the PTHR1 gene. These results indicate that the PTHR1 gene is not, in contrast to previous suggestions, the culprit for enchondromatosis.
The Variable Manifestations of Multiple Enchondromatosis
AbstractRoentgenograms taken over a 20-year period illustrate the authors' findings in 2 cases of multiple enchondromatosis. X-ray findings at time of diagnosis were similar in the 2 patients but varied from those considered characteristic of Ollier's disease. With growth, a tendency toward spontaneous arrest and even regression of the disease was noted. Roentgenograms of 3 other patients with the disease, of varying severity, were available, permitting a review of the variety of changes in this condition. The differentiation of enchondromatosis and metaphyseal dysostosis is discussed at length.
American Journal of Medical Genetics Part C Seminars in Medical Genetics · 2012 · 42 citations
Enchondromatosis revisited: New classification with molecular basis
AbstractThe so-called "enchondromatoses" are skeletal disorders defined by the presence of ectopic cartilaginous tissue within bone tissue. The clinical and radiographic features of the different enchondromatoses are distinct, and grouping them does not reflect a common pathogenesis but simply a similar radiographic appearance and thus the need for a differential diagnosis. Recent advances in the understanding of their molecular and cellular bases confirm the heterogeneous nature of the different enchondromatoses. Some, like Ollier disease, Maffucci disease, metaphyseal chondromatosis with hydroxyglutaric aciduria, and metachondromatosis are produced by a dysregulation of chondrocyte proliferation, while others (such as spondyloenchondrodysplasia or dysspondyloenchondromatosis) are caused by defects in structure or metabolism of cartilage or bone matrix. In other forms (e.g., the dominantly inherited genochondromatoses), the basic defect remains to be determined. The classification, proposed by Spranger and associates in 1978 and tentatively revised twice, was based on the radiographic appearance, the anatomic sites involved, and the mode of inheritance. The new classification proposed here integrates the molecular genetic advances and delineates phenotypic families based on the molecular defects. Reference radiographs are provided to help in the diagnosis of the well-defined forms. In spite of advances, many cases remain difficult to diagnose and classify, implying that more variants remain to be defined at both the clinical and molecular levels.
Proceedings of the International Conference on Parallel Processing · 1988 · 27 citations
Reliability of the Hypercube.
AbstractEnchondromas are a common tumor in bone that can occur as multiple lesions in enchondromatosis, which is associated with deformity of the affected bone. These lesions harbor somatic mutations in IDH and driving expression of a mutant Idh1 in Col2 expressing cells in mice causes an enchondromatosis phenotype. Here we compared growth plates from E18.5 mice expressing a mutant Idh1 with control littermates using single cell RNA sequencing. Data from Col2 expressing cells were analysed using UMAP and RNA pseudo-time analyses. A unique cluster of cells was identified in the mutant growth plates that expressed genes known to be upregulated in enchondromas. There was also a cluster of cells that was underrepresented in the mutant growth plates that expressed genes known to be important in longitudinal bone growth. Immunofluorescence showed that the genes from the unique cluster identified in the mutant growth plates were expressed in multiple growth plate anatomic zones, and pseudo-time analysis also suggested these cells could arise from multiple growth plate chondrocyte subpopulations. This data supports the notion that a subpopulation of chondrocytes become enchondromas at the expense of contributing to longitudinal growth.
Scientific Reports · 2024 · 1 citations · open access
Single cell analysis of Idh mutant growth plates identifies cell populations responsible for longitudinal bone growth and enchondroma formation
AbstractEnchondromas are a common tumor in bone that can occur as multiple lesions in enchondromatosis, which is associated with deformity of the affected bone. These lesions harbor somatic mutations in IDH and driving expression of a mutant Idh1 in Col2 expressing cells in mice causes an enchondromatosis phenotype. Here we compared growth plates from E18.5 mice expressing a mutant Idh1 with control littermates using single cell RNA sequencing. Data from Col2 expressing cells were analysed using UMAP and RNA pseudo-time analyses. A unique cluster of cells was identified in the mutant growth plates that expressed genes known to be upregulated in enchondromas. There was also a cluster of cells that was underrepresented in the mutant growth plates that expressed genes known to be important in longitudinal bone growth. Immunofluorescence showed that the genes from the unique cluster identified in the mutant growth plates were expressed in multiple growth plate anatomic zones, and pseudo-time analysis also suggested these cells could arise from multiple growth plate chondrocyte subpopulations. This data supports the notion that a subpopulation of chondrocytes become enchondromas at the expense of contributing to longitudinal growth.
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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