DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Phelan-McDermid syndrome — 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 modulePhelan-McDermid syndrome 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 phelan-mcdermid 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
collagen type IV alpha 5 chain (COL4A5) — COL4A5 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 pgedrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6WKU · 1.76 Å · ligand TRIETHYLENE GLYCOL (PGE). Experimental structure, not a prediction.
What the evidence adds up to
In a 2016 study, quantitative proteomics in Shank3-deficient neurons identified increased steady-state levels of the kinase CLK2, which enhanced phosphorylation of the PP2A regulatory subunit B56β and down-regulated Akt–mTORC1 signalling. Pharmacological or genetic inhibition of CLK2, or activation of Akt, relieved synaptic deficits in Shank3-deficient and Phelan-McDermid syndrome patient-derived neurons. CLK2 inhibition also restored normal sociability in a Shank3-deficient mouse model. No human trial of a CLK2 inhibitor has been reported.
Phelan-McDermid syndrome is generally caused by a heterozygous microdeletion of contiguous genes on distal 22q, including SHANK3, or by sequence variants of SHANK3. Haploinsufficiency of SHANK3 is considered the main cause. The phenotype is variable and lacks a distinctive characteristic, so clinical diagnosis must be confirmed by genetic analysis. A 2022 review discussed risperidone, intranasal insulin, insulin growth factor 1, and oxytocin as potential therapeutic options, but provided no efficacy data from controlled trials. A 2018 case report described a 30-year-old woman with a 22q13.33 deletion whose psychotic alterations were repeatedly triggered by mild fever episodes.
A 2021 review noted that PMS is easy to misdiagnose due to the lack of specific clinical manifestations, and that other genes in the 22q13 region may contribute to symptom formation. The same review emphasised that SHANK3 is the critical candidate gene for neurological features. What is still missing are controlled clinical trials for any proposed treatment, patient stratification by deletion size or genetic variant, and funding for natural history studies that could define endpoints for future trials.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Science · 2016 · 157 citations
CLK2 inhibition ameliorates autistic features associated with SHANK3 deficiency
AbstractSH3 and multiple ankyrin repeat domains 3 (SHANK3) haploinsufficiency is causative for the neurological features of Phelan-McDermid syndrome (PMDS), including a high risk of autism spectrum disorder (ASD). We used unbiased, quantitative proteomics to identify changes in the phosphoproteome of Shank3-deficient neurons. Down-regulation of protein kinase B (PKB/Akt)-mammalian target of rapamycin complex 1 (mTORC1) signaling resulted from enhanced phosphorylation and activation of serine/threonine protein phosphatase 2A (PP2A) regulatory subunit, B56β, due to increased steady-state levels of its kinase, Cdc2-like kinase 2 (CLK2). Pharmacological and genetic activation of Akt or inhibition of CLK2 relieved synaptic deficits in Shank3-deficient and PMDS patient-derived neurons. CLK2 inhibition also restored normal sociability in a Shank3-deficient mouse model. Our study thereby provides a novel mechanistic and potentially therapeutic understanding of deregulated signaling downstream of Shank3 deficiency.
Clinical and Genetic Aspects of Phelan–McDermid Syndrome: An Interdisciplinary Approach to Management
AbstractPhelan–McDermid syndrome (PMS) is a rare, heterogeneous, and complex neurodevelopmental disorder. It is generally caused by a heterozygous microdeletion of contiguous genes located in the distal portion of the long arm of chromosome 22, including the SHANK3 gene. Sequence variants of SHANK3, including frameshift, nonsense mutations, small indels and splice site mutations also result in PMS. Furthermore, haploinsufficiency in SHANK3 has been suggested as the main cause of PMS. SHANK3 is also associated with intellectual disability, autism spectrum disorder and schizophrenia. The phenotype of PMS is variable, and lacks a distinctive phenotypic characteristic, so the clinical diagnosis should be confirmed by genetic analysis. PMS is a multi-system disorder, and clinical care must encompass various specialties and therapists. The role of risperidone, intranasal insulin, insulin growth factor 1, and oxytocin as potential therapeutic options in PMS will be discussed in this review. The diagnosis of PMS is important to provide an appropriate clinical evaluation, treatment, and genetic counseling.
Phelan-McDermid syndrome in adult patient with atypical bipolar psychosis repeatedly triggered by febrility
AbstractPhelan-McDermid syndrome (PMD) is a rare genetic condition with only a few cases describing patients diagnosed as adults. We describe a long diagnostic odyssey of a 30-year-old woman who was diagnosed with Phelan-McDermid syndrom. Array comparative genomic hybridization analysis confirmed a 22q13.33 deletion, encompassing exon 9-23 of the SHANK3 gene and exon 1 of the ACR gene. We provide an uncommon feature of the disease, where psychotic alteration is repeatedly triggered by the same physical factor in our patient - mild fever episodes.
[Advance of research on Phelan-McDermid syndrome].
AbstractPhelan-McDermid syndrome (PMS)(OMIM#606232) is a rare genetic disorder caused by a deletion of the distal long arm of chromosome 22q13 involving a variety of clinical features with considerably heterogeneous degrees of severity. This syndrome is characterized by global developmental delay, intellectual disability, hypotonia, absent or severely delayed speech, minor dysmorphic features and autism spectrum disorder. PMS is easy to be misdiagnosed due to the lack of specific clinical manifestations. SHANK3 has been identified as the critical candidate gene for the neurological features of this syndrome. However, some studies have shown that other genes located in the 22q13 region may have a role in the formation of symptoms in individuals with PMS. This article provides a review for recent progress made in research on PMS including etiology, clinical manifestation, diagnosis, and treatment, with a particular emphasis on clinical diagnosis and treatment.
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.
