DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for holoprosencephaly — screening already-approved drugs against its 18-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleHoloprosencephaly maps to a 18-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 holoprosencephaly 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
nuclear receptor binding SET domain protein 1 (NSD1) — NSD1 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 samdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3OOI · 1.75 Å · ligand S-ADENOSYLMETHIONINE (SAM). Experimental structure, not a prediction.
What the evidence adds up to
Two new mouse mutants with a holoprosencephaly-like phenotype were described in 2012. Both mutations disrupt genes in the GPI biosynthesis pathway: gonzo disrupts Pign and beaker disrupts Pgap1. In these mutants, GPI-anchored proteins are mislocalised. The GPI-anchored protein Cripto (mouse) and its human ortholog TDGF1 are known to cause holoprosencephaly when disrupted, and the authors show that TGFβ signalling is reduced both in vitro and in vivo in the GPI mutants. The work suggests that GPI biosynthesis genes should be screened for association with human holoprosencephaly. No human trial or therapeutic intervention was tested.
A 2014 study generated knockout mice for the ubiquitin E3 ligase NOSIP. Loss of NOSIP in mice causes holoprosencephaly and facial anomalies including cleft lip/palate, cyclopia and facial midline clefting. NOSIP was identified as a novel interaction partner of protein phosphatase PP2A; NOSIP mediates monoubiquitination of the PP2A catalytic subunit, and loss of NOSIP results in an increase in PP2A activity in craniofacial tissue in the knockout mice. The authors conclude that NOSIP is a candidate gene for holoprosencephaly in humans. No human data or treatment are reported.
A 2018 review describes holoprosencephaly as a spectrum of malformations related to incomplete separation of the prosencephalon, with wide clinical variability depending on the imaging subtype. Early postnatal lethality is common, but a significant fraction of newborns diagnosed with HPE survive into childhood and even adulthood. The review covers clinical management from the prenatal period to adulthood but does not report any new drug or intervention.
What is still missing: no drug has been tested in any animal model or human patient for holoprosencephaly in these abstracts. There is no clinical trial, no repurposing candidate, and no therapeutic strategy. The genetic mechanisms described (GPI anchor defects, NOSIP-PP2A interaction) remain at the level of basic mouse biology. Human screening studies for GPI biosynthesis genes or NOSIP in holoprosencephaly cohorts have not been reported. Funding for such screening, a feasible trial design, and patient stratification by genetic subtype are all 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.
Biology Open · 2012 · 52 citations · open access
Defects in GPI biosynthesis perturb Cripto signaling during forebrain development in two new mouse models of holoprosencephaly
AbstractHoloprosencephaly is the most common forebrain defect in humans. We describe two novel mouse mutants that display a holoprosencephaly-like phenotype. Both mutations disrupt genes in the glycerophosphatidyl inositol (GPI) biosynthesis pathway: gonzo disrupts Pign and beaker disrupts Pgap1. GPI anchors normally target and anchor a diverse group of proteins to lipid raft domains. Mechanistically we show that GPI anchored proteins are mislocalized in GPI biosynthesis mutants. Disruption of the GPI-anchored protein Cripto (mouse) and TDGF1 (human ortholog) have been shown to result in holoprosencephaly, leading to our hypothesis that Cripto is the key GPI anchored protein whose altered function results in an HPE-like phenotype. Cripto is an obligate Nodal co-factor involved in TGFβ signaling, and we show that TGFβ signaling is reduced both in vitro and in vivo. This work demonstrates the importance of the GPI anchor in normal forebrain development and suggests that GPI biosynthesis genes should be screened for association with human holoprosencephaly.
American Journal of Medical Genetics Part C Seminars in Medical Genetics · 2018 · 20 citations
Holoprosencephaly from conception to adulthood
AbstractHoloprosencephaly (HPE) consists of a spectrum of malformations related to incomplete separation of the prosencephalon. There is a wide clinical variability depending on the HPE subtype seen on imaging. Early postnatal lethality is common, however a significant fraction of newborns diagnosed with HPE will survive into childhood and even adulthood. Here we will review the clinical management of HPE during different ages from the prenatal period to adulthood.
The Ubiquitin E3 Ligase NOSIP Modulates Protein Phosphatase 2A Activity in Craniofacial Development
AbstractHoloprosencephaly is a common developmental disorder in humans characterised by incomplete brain hemisphere separation and midface anomalies. The etiology of holoprosencephaly is heterogeneous with environmental and genetic causes, but for a majority of holoprosencephaly cases the genes associated with the pathogenesis could not be identified so far. Here we report the generation of knockout mice for the ubiquitin E3 ligase NOSIP. The loss of NOSIP in mice causes holoprosencephaly and facial anomalies including cleft lip/palate, cyclopia and facial midline clefting. By a mass spectrometry based protein interaction screen we identified NOSIP as a novel interaction partner of protein phosphatase PP2A. NOSIP mediates the monoubiquitination of the PP2A catalytic subunit and the loss of NOSIP results in an increase in PP2A activity in craniofacial tissue in NOSIP knockout mice. We conclude, that NOSIP is a critical modulator of brain and craniofacial development in mice and a candidate gene for holoprosencephaly in humans.
Revista de lenguas y literaturas catalana gallega y vasca · 2010 · 0 citations · open access
Livro dos Feitos, ed. de Luciano José Vianna y Ricardo da Costa
AbstractHoloprosencephaly is a common developmental disorder in humans characterised by incomplete brain hemisphere separation and midface anomalies. The etiology of holoprosencephaly is heterogeneous with environmental and genetic causes, but for a majority of holoprosencephaly cases the genes associated with the pathogenesis could not be identified so far. Here we report the generation of knockout mice for the ubiquitin E3 ligase NOSIP. The loss of NOSIP in mice causes holoprosencephaly and facial anomalies including cleft lip/palate, cyclopia and facial midline clefting. By a mass spectrometry based protein interaction screen we identified NOSIP as a novel interaction partner of protein phosphatase PP2A. NOSIP mediates the monoubiquitination of the PP2A catalytic subunit and the loss of NOSIP results in an increase in PP2A activity in craniofacial tissue in NOSIP knockout mice. We conclude, that NOSIP is a critical modulator of brain and craniofacial development in mice and a candidate gene for holoprosencephaly in humans.
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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