DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for lissencephaly due to LIS1 mutation — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleLissencephaly due to LIS1 mutation maps to a 2-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 lissencephaly due to lis1 mutation 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
tubulin alpha 1a (TUBA1A) — TUBA1A 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 gtpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9WD9 · 2.26 Å · ligand GUANOSINE-5'-TRIPHOSPHATE (GTP). Experimental structure, not a prediction.
What the evidence adds up to
In a retrospective study of 63 patients with posteriorly predominant lissencephaly, 40 carried LIS1 point mutations (77.5%) or small genomic deletions (20%), and one carried a somatic nonsense mutation. Most LIS1-mutation patients had posterior agyria (grade 3a, 55.3%), a thin corpus callosum (50%), and prominent perivascular spaces (67.4%). Tetraplegia occurred in 61.1%, early seizures in 82.9%, and more-than-daily seizures in 48.7%. Neither mutation type nor location predicted severity of the lissencephaly. Patients without LIS1 mutations tended to have less severe lissencephaly (grade 4a, 41.6%) and no additional brain abnormalities.
Five patients with LIS1 missense mutations showed a wider and milder spectrum of cortical malformations and clinical outcomes compared with patients carrying other mutation types. One such patient had normal intelligence. The authors attribute this to suboptimal function of the mutant LIS1 protein rather than complete loss of function, and suggest that underascertainment of patients with subtle malformations means LIS1 abnormalities may account for a broader range of childhood neurologic problems than previously recognised.
In a separate cohort of 15 patients with classic lissencephaly and subcortical band heterotopia, one patient with a 1385A→C mutation in LIS1 had lissencephaly more severe than expected for a missense mutation. The authors propose that the mutation site, in a functionally critical region of the protein, explains the unusually severe phenotype.
No drug treatment is mentioned in any of these abstracts. What is missing is any clinical trial, any preclinical drug screen, any animal model testing a compound against LIS1-related lissencephaly, and any funding or trial design aimed at repurposing an existing drug for this condition. Patient stratification by mutation type and residual protein function may be necessary before any therapy could be tested.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Archives of Neurology · 2009 · 100 citations · open access
LIS1-Related Isolated Lissencephaly
AbstractOBJECTIVE: With the largest data set of patients with LIS1-related lissencephaly, the major cause of posteriorly predominant lissencephaly related to either LIS1 mutation or intragenic deletion, described so far, we aimed to refine the spectrum of neurological and radiological features and to assess relationships with the genotype. DESIGN: Retrospective study. Subjects A total of 63 patients with posteriorly predominant lissencephaly. INTERVENTIONS: Of the 63 patients, 40 were found to carry either LIS1 point mutations (77.5%) or small genomic deletions (20%), and 1 carried a somatic nonsense mutation. On the basis of the severity of neuromotor impairment, epilepsy, and radiological findings, correlations with the location and type of mutation were examined. RESULTS: Most patients with LIS1 mutations demonstrated posterior agyria (grade 3a, 55.3%) with thin corpus callosum (50%) and prominent perivascular spaces (67.4%). By contrast, patients without LIS1 mutations tended to have less severe lissencephaly (grade 4a, 41.6%) and no additional brain abnormalities. The degree of neuromotor impairment was in accordance with the severity of lissencephaly, with a high incidence of tetraplegia (61.1%). Conversely, the severity of epilepsy was not determined with the same reliability because 82.9% had early onset of seizures and 48.7% had seizures more often than daily. In addition, neither the mutation type nor the location of the mutation were found to predict the severity of LIS1-related lissencephaly. CONCLUSION: Our results confirm the homogeneity profile of patients with LIS1-related lissencephaly who demonstrate in a large proportion Dobyns lissencephaly grade 3a, and the absence of correlation with LIS1 mutations.
<i>LIS1</i> missense mutations cause milder lissencephaly phenotypes including a child with normal IQ
AbstractBACKGROUND: Classical lissencephaly is a disorder of neuroblast migration with most patients having mutations of either the LIS1 or DCX genes. Most patients with lissencephaly secondary to LIS1 mutations have a severe malformation consisting of generalized agyria and pachygyria. However, increasing experience suggests that the phenotypic spectrum is wider than previously thought. METHODS: The authors describe the clinical and imaging features and mutation data of the five known patients with missense mutations of the LIS1 gene and emphasize one patient with normal intelligence. RESULTS: Patients with a missense mutation of the LIS1 gene have a wider and milder spectrum of cortical malformations and clinical sequelae compared with patients with other mutation types. CONCLUSION: Milder and more variable phenotypes seen in patients with missense mutations of LIS1 are likely a consequence of suboptimal function of the mutant LIS1 protein, rather than complete loss of function of this protein. The authors suggest that the few patients found thus far with missense mutations of LIS1 results from an underascertainment of patients with more subtle malformations and that abnormalities of the LIS1 gene may account for a greater spectrum of neurologic problems in childhood than has previously been appreciated.
Mutation screening in a cohort of patients with lissencephaly and subcortical band heterotopia
AbstractThe authors describe clinical, neuroimaging and molecular findings in a group of 15 patients with classic lissencephaly (LIS) and subcortical band heterotopia (SBH). A 1385A-->C mutation was found in the LIS1 gene in one patient with LIS more severe than expected for individuals with missense mutations in LIS1. The authors believe that the site of the mutation, present in a functionally critical region of the protein, could explain the unusual severe phenotype found in this patient.
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.
