DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Larsen syndrome — 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 moduleLarsen syndrome 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 larsen syndrome 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
fibroblast growth factor receptor 3 (FGFR3) — FGFR3 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 acpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4K33 · 2.3405 Å · ligand PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER (ACP). Experimental structure, not a prediction.
What the evidence adds up to
Larsen syndrome is a rare skeletal disorder with an estimated prevalence of one in 100,000 live births. It is characterised by congenital dislocations of multiple large joints, distinct facial features (flattened face, short nose, broad depressed nasal bridge, prominent forehead), and spinal abnormalities that can include severe cervical kyphosis and vertebral malformations. Cleft palate, hearing loss, and foot deformities are occasionally observed. Two case reports describe spinal cord compromise: an 18-month-old female with severe cervical kyphosis causing spinal cord compression and upper motor neuron signs, and a 14-year-old male with amyotrophy of the right hand and lower motor neuron signs from spinal malformations. The authors of that 2008 report conclude that spinal cord compression requires surgical treatment in early life.
The disorder is caused by missense or small in-frame deletions in the FLNB gene. A 2006 study found FLNB mutations in all five cases tested, and by compiling data from two studies observed clustering within three filamin B protein domains: the calponin homology 2 domain, repeat 14, and repeat 15. The authors suggested that screening as few as five of the 46 coding exons could detect mutations. A 2016 study of seven patients (five sporadic, one mother-son duo) identified five novel mutations and confirmed immunoglobulin-like repeats 14 and 15 as major hotspot regions, while also adding repeat 5 as a newly affected domain. All patients had a uniform clinical phenotype, though two showed delayed carpal ossification rather than the widely described advanced carpal ossification. The authors note that all reported mutations leave the filamin B protein intact, consistent with a gain-of-function effect.
Management of multiple large-joint dislocations is difficult, with a tendency toward recurrence. A 2015 case report describes a boy treated with ten orthopaedic procedures over 12 years of follow-up, but the outcome was not satisfactory. Patients often require multiple corrective surgeries and repeated anaesthesia. A 2024 document on anaesthetic considerations for Larsen syndrome states that complex surgeries are difficult without certain medications, but provides no clinical data or outcomes.
What is still missing is a systematic, prospective study of surgical outcomes with standardised reporting, a larger patient series to quantify the mutation detection rate and genotype-phenotype correlations, and any clinical trial of a medical or surgical intervention that demonstrates improved functional outcomes. No drug therapy is mentioned in any of 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.
Journal of Medical Genetics · 2006 · 50 citations · open access
Mutations responsible for Larsen syndrome cluster in the FLNB protein
AbstractBACKGROUND: A gene for Larsen syndrome was recently described, and mutations were reported in five cases. OBJECTIVE: To test whether mutations in this gene, FLNB, could explain the disease in our independent collection of sporadic and dominant Larsen syndrome cases; and to test whether mutations occurred in a non-random pattern. RESULTS: Missense mutations were found in each of five cases. Four of the five were new; one was reported in a sporadic case in the original Larsen syndrome study of five cases. All mutations from the two studies were compiled. Clustered mutations were observed within three filamin B protein domains: the calponin homology 2 domain, repeat 14, and repeat 15. This suggested that as few as five (of the total of 46) coding exons of FLNB could be screened to detect Larsen syndrome mutations. Four of these exons were screened in a sixth (sporadic) case and a previously reported G1691S substitution mutation detected. CONCLUSIONS: Mutations in FLNB may be responsible for all cases of Larsen syndrome. They appear to occur in specific functional domains of the filamin B protein. This should simplify diagnostic screening of the FLNB gene. Analyses in larger patient series are warranted to quantify this. The study confirmed the extreme variability in clinical presentation and the presence of unaffected carriers. A molecular screen would be valuable for diagnosis and genetic counselling.
BMC Medical Genetics · 2016 · 33 citations · open access
Phenotype and genotype in patients with Larsen syndrome: clinical homogeneity and allelic heterogeneity in seven patients
AbstractBACKGROUND: Larsen syndrome is an autosomal dominant skeletal dysplasia characterized by large joint dislocations and craniofacial dysmorphism. It is caused by missense or small in-frame deletions in the FLNB gene. To further characterize the phenotype and the mutation spectrum of this condition, we investigated seven probands, five sporadic individuals and a mother-son-duo with Larsen syndrome. METHODS: The seven patients from six unrelated families were clinically and radiologically evaluated. All patients were screened for mutations in selected exons and exon-intron boundaries of the FLNB gene by Sanger sequencing. FLNB transcript analysis was carried out in one patient to analyse the effect of the sequence variant on pre-mRNA splicing. RESULTS: All patients exhibited typical facial features and joint dislocations. Contrary to the widely described advanced carpal ossification, we noted delay in two patients. We identified the five novel mutations c.4927G A/p.(Gly1643Ser), c.4876G > T / p.(Gly1626Trp), c.4664G > A / p.(Gly1555Asp), c.2055G > C / p.Gln685delins10 and c.5021C > T / p.(Ala1674Val) as well as a frequently observed mutation in Larsen syndrome [c.5164G > A/p.(Gly1722Ser)] in the hotspot regions. FLNB transcript analysis of the c.2055G > C variant revealed insertion of 27 bp intronic sequence between exon 13 and 14 which gives rise to in-frame deletion of glutamine 685 and insertion of ten novel amino acid residues (p.Gln685delins10). CONCLUSIONS: All seven individuals with Larsen syndrome had a uniform clinical phenotype except for delayed carpal ossification in two of them. Our study reveals five novel FLNB mutations and confirms immunoglobulin-like (Ig) repeats 14 and 15 as major hotspot regions. The p.Gln685delins10 mutation is the first Larsen syndrome-associated alteration located in Ig repeat 5. All mutations reported so far leave the filamin B protein intact in accordance with a gain-of-function effect. Our findings underscore the characteristic clinical picture of FLNB-associated Larsen syndrome and add Ig repeat 5 to the filamin B domains affected by the clustered mutations.
Journal of Pediatric Orthopaedics B · 2015 · 5 citations
Presumed Larsen syndrome in a child
AbstractLarsen syndrome (OMIM 150250) was first described in 1950 as an entity characterized by distinct facial features and dislocations of the multiple large joint, and cleft palate, hearing loss, and spinal abnormalities were occasionally observed. The prevalence of Larsen syndrome is estimated to be one in 100,000 live births . Management of multiple large-joint dislocations often proves difficult with a tendency toward recurrence, particularly if a patient has complete dislocation of the knee .We treated a boy with the clinical phenotype of Larsen syndrome using 10 orthopedic procedures, but failed to achieve a satisfactory outcome.The aim of this report is to review the surgical course and report results of surgical treatments for this patient with 12 years of follow-up.
Síndrome de Larsen: a propósito de dos casos con afectación medular
AbstractINTRODUCTION: Larsen syndrome is characterised by untreatable congenital dislocation of multiple body joints, along with marked foot deformities. These patients have a flattened face with a short nose, a broad depressed nasal bridge and a prominent forehead. In this clinical note our aim is to report two cases that coursed with spinal cord compromise. CASE REPORTS: Case 1: an 18-month-old female with congenital dislocation of knees and hips. The patient had a flat face, sunken root of nose, and carp mouth. Magnetic resonance imaging of the spine showed severe cervical kyphosis secondary to malformation and hypoplasia of the cervical vertebral bodies and important compression of the spinal cord. Clinically, there were also signs of upper motor neuron syndrome, which was especially prominent in the lower limbs. Case 2: a 14-year-old male with a characteristic face and dislocation of the head of the radius. The patient presented amyotrophy of the muscles in the right hand and clinical signs of lower motor neuron syndrome due to neuronal damage secondary to spinal malformations. CONCLUSIONS: Larsen syndrome is an infrequent osteochondrodysplasia. Alteration of the spine is common and may give rise to spinal cord compression with varying clinical repercussions which require surgical treatment in the early years of the patient's life.
Zenodo (CERN European Organization for Nuclear Research) · 2024 · 0 citations · open access
larsen anestesia pdf download
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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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