DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for osteosclerotic metaphyseal dysplasia — 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 moduleOsteosclerotic metaphyseal dysplasia 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 osteosclerotic metaphyseal dysplasia 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
leucine rich repeat kinase 1 (LRRK1) — LRRK1 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 gdpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8FAC · 3.92 Å · ligand GUANOSINE-5'-DIPHOSPHATE (GDP). Experimental structure, not a prediction.
What the evidence adds up to
Osteosclerotic metaphyseal dysplasia (OSMD) is a very rare autosomal-recessive sclerosing skeletal dysplasia. In 2016, whole exome sequencing in a boy with OSMD identified a homozygous 7 bp deletion in the LRRK1 gene, predicted to result in an elongated protein lacking part of its WD40 domains. In vitro functional studies using osteoclasts from Lrrk1-deficient mice showed the deletion was a loss-of-function mutation. Genetic analysis of two unrelated patients suggested OSMD is a genetically heterogeneous condition. A 2023 report described a 40-year-old man with a homozygous, likely pathogenic LRRK1 variant who had multiple peripheral low-energy trauma fractures since puberty, short stature (167 cm; −1.5 SD), and no other complaints. His bone mineral density was high, and X-rays showed osteosclerosis of the metaphyses of long bones and vertebrae. The authors noted that phenotypic features such as short stature, pathological fractures, delayed development, and hypotonia are not uniformly present.
No drug treatment for OSMD is mentioned in any of these abstracts. The 2020 review of skeletal dysplasia treatments discusses pharmacological approaches for achondroplasia, fibrodysplasia ossificans progressiva, metaphyseal dysplasia type Schmid, pseudoachondroplasia, hypophosphatasia, and Morquio A disease, but does not list OSMD among conditions with emerging therapies. The 2018 paper on Schmid metaphyseal chondrodysplasia describes orthopaedic interventions—valgus osteotomy after physeal closure for coxa vara, and hemiepiphysiodesis for genu varum—but that is a different disorder caused by COL10A1 mutations, not OSMD. The 1991 review states that early recognition and prevention of complications remain the mainstay of management for skeletal dysplasias generally, and that operative bone lengthening was then being evaluated.
What is missing for OSMD specifically: no clinical trials, no pharmacological or enzyme replacement strategies, no gene therapy approaches have been reported. The genetic basis is only partially understood, with locus heterogeneity suggested but not fully characterised. Patient numbers are extremely small, and natural history data are limited to case reports. Any future treatment would require basic preclinical work, a larger patient registry to understand phenotypic variation, and funding for drug screening or gene therapy development.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Therapeutic Advances in Endocrinology and Metabolism · 2020 · 50 citations · open access
New perspectives on the treatment of skeletal dysplasia
AbstractThe last few decades have been marked by the identification of numerous genes implicated in genetic disorders, helping in the elucidation of the underlying pathophysiology of these conditions. This has allowed new therapeutic approaches to emerge such as cellular therapy, gene therapy, or pharmacological therapy for various conditions. Skeletal dysplasias are good models to illustrate these scientific advances. Indeed, several therapeutic strategies are currently being investigated in osteogenesis imperfecta; there are ongoing clinical trials based on pharmacological approaches, targeting signaling pathways in achondroplasia and fibrodysplasia ossificans progressiva or the endoplasmic reticulum stress in metaphyseal dysplasia type Schmid or pseudoachondroplasia. Moreover, the treatment of hypophosphatasia or Morquio A disease illustrates the efficacy of enzyme drug replacement. To provide a highly specialized multidisciplinary approach, these treatments are managed by reference centers. The emergence of treatments in skeletal dysplasia provides new perspectives on the prognosis of these severe conditions and may change prenatal counseling in these diseases over the coming years.
Journal of Medical Genetics · 2016 · 49 citations · open access
Identification of biallelic <i>LRRK1</i> mutations in osteosclerotic metaphyseal dysplasia and evidence for locus heterogeneity
AbstractBACKGROUND: Osteosclerotic metaphyseal dysplasia (OSMD) is a unique form of osteopetrosis characterised by severe osteosclerosis localised to the bone ends. The mode of inheritance is autosomal recessive. Its genetic basis is not known. OBJECTIVE: To identify the disease gene for OSMD. METHODS AND RESULTS: By whole exome sequencing in a boy with OSMD, we identified a homozygous 7 bp deletion (c.5938_5944delGAGTGGT) in the LRRK1 gene. His skeletal phenotype recapitulated that seen in the Lrrk1-deficient mouse. The shared skeletal hallmarks included severe sclerosis in the undermodelled metaphyses and epiphyseal margins of the tubular bones, costal ends, vertebral endplates and margins of the flat bones. The deletion is predicted to result in an elongated LRRK1 protein (p.E1980Afs*66) that lacks a part of its WD40 domains. In vitro functional studies using osteoclasts from Lrrk1-deficient mice showed that the deletion was a loss of function mutation. Genetic analysis of LRRK1 in two unrelated patients with OSMD suggested that OSMD is a genetically heterogeneous condition. CONCLUSIONS: This is the first study to identify the causative gene of OSMD. Our study provides evidence that LRRK1 plays a critical role in the regulation of bone mass in humans.
Orthopaedic Surgery · 2018 · 29 citations · open access
Schmid's Type of Metaphyseal Chondrodysplasia: Diagnosis and Management
AbstractOBJECTIVES: There are several types of metaphyseal chondrodysplasia and various clinical types have been differentiated. The Schmid type of metaphyseal chondrodysplasia is the most common. Diffuse metaphyseal flaring, irregularity, and growth plate widening, which are most severe in the knees, are the most striking radiological features of this disease. The Schmid type of metaphyseal dysostosis is characterized by failure of normal mineralization of the zone of provisional calcification, leading to widened physes and enlarged knobby metaphyses, effectively causing shortening of the tubular bones, splaying of the metaphyses, coxa vara, and bow legs. Orthopaedic interventions were primarily performed on the lower extremities. METHODS: Twelve children (seven girls and five boys) aged 7-10 years were enrolled in this study. Moderate short stature was a uniform feature associated with predominant involvement of the proximal femora and bow legs resulted in the development of angular deformities. A waddling gait was a consequence of coxa vara in eight children. Valgus osteotomy of the proximal femur was planned after physeal closure for the group of children with coxa vara. Hemiepiphysiodesis was performed to re-align the genu varum in three children. RESULTS: Other forms of metaphyseal dysostosis were ruled based on full clinical and radiographic phenotypes, with confirmation through molecular pathology. Mutations in the COL10A1 gene located on chromosome 6q21-q22.3 were confirmed. Re-alignment was accomplished in our group of patients. CONCLUSION: The most striking clinical features of Schmid metaphyseal chondrodysplasia which appear within the first 2-3 years of life are: moderate short limbs and short stature, a waddling gait, and increasing shortness of stature with age. The Schmid type of metaphyseal chondrodysplasia is a disorder that arises from defective type X collagen, which is typically found in the hypertrophic zone of the physes. Moderate short stature and a waddling gait associated with pain are the most common clinical presentations. Osteotomies to correct bow legs are sometimes combined with lengthening procedures. Recurrence of the deformities with growth is not uncommon; therefore, hemiepiphysiodesis or stapling might be indicated in some cases.
Journal of Paediatrics and Child Health · 1972 · 4 citations
SPONDYLO‐METAPHYSEAL DYSPLASIA
AbstractSYNOPSIS A case of 7 year old Danish girl with spondylo‐metaphyseal dysplasia is reported. The disease is characterised clinically by shortening of stature and thoracic kyphosis. The radiographic pattern of the vertebral column, metaphyses and round bones of the hands and feet, is diagnostic in this syndrome. Degenerative bone changes supervene early in adult life.
Current Opinion in Pediatrics · 1991 · 0 citations
Skeletal dysplasias in children
AbstractNewly delineated skeletal dysplasias include some metaphyseal dysplasias, forms of chondrodysplasia punctata, and expansile osteolysis. Spondylometaphyseal dysplasias and neonatally lethal chondrodysplasias have been reclassified. Osteogenesis imperfecta and some spondyloepiphyseal dysplasias are disorders of type I and type II collagen, respectively. Early recognition and prevention of complications of skeletal dysplasias remain the mainstay of management. Operative bone lengthening is currently being evaluated in some skeletal dysplasias.
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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