DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for pontocerebellar hypoplasia — screening already-approved drugs against its 15-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease modulePontocerebellar hypoplasia maps to a 15-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 pontocerebellar hypoplasia 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
calcium/calmodulin dependent serine protein kinase (CASK) — CASK 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 2r,3s,4r,5rdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3C0I · 1.85 Å · ligand [(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] dihydrogen phosphate (3AM). Experimental structure, not a prediction.
What the evidence adds up to
Pontocerebellar hypoplasia is a group of autosomal recessive neurodegenerative disorders with prenatal onset, characterised by cerebellar hypoplasia and variable atrophy of the cerebellum and ventral pons, often with supratentorial involvement including neocortical atrophy, ventriculomegaly and microcephaly. In a cohort of 169 patients from 141 families, 106 tested positive for mutations in TSEN54, TSEN2, TSEN34 or RARS2. A strong correlation was found between TSEN54 mutations and a dragonfly-like cerebellar pattern on MRI, where the cerebellar hemispheres are flat and severely reduced while the vermis is relatively spared. Clinically, TSEN54 mutations are associated with dyskinesia or dystonia and variable spasticity, and nonsense or splice site mutations predict a more severe phenotype with perinatal symptoms, ventilator dependency and early death. Ten new mutations in TSEN54, TSEN2 and RARS2 were reported, and RARS2 mutations were linked to pontocerebellar hypoplasia type 1 with elevated cerebrospinal fluid lactate.
Two unrelated patients with pontocerebellar hypoplasia type 2 were found to carry novel TSEN54 mutations: a missense mutation c.355T>G/p.Y119D in compound heterozygosity with the common c.919G>T/p.A307S, and a novel homozygous c.7ins6(CCGGAG)/p.E2-P3insPE variant. These expanded the mutation spectrum and suggested that an expanded array of mutations might help define differences in severity and phenotype-genotype correlations, but no survival or response data were reported for these patients.
A single case report described a child with a heterozygote mutation in exon 8 of TSEN54 and in exon 1 of EXOSC3, a combination not previously represented. The child had seizures, feeding and swallowing disorders, strabismus, kyphoscoliosis, poor balance and coordination, mental retardation, severe speech impairment, hypotonia, and distinctive dysmorphic features including brachycephalia, protruding brow arcs, preauricular excrescence, medial eyebrow flare, hypoplasia of the lower face, large nose, and eyelid ptosis. MRI showed microgyria, pontocerebellar hypoplasia, corpus callosum hypoplasia, and TH4 rachischisis; ultrasound revealed thymomegaly and septal defects. EEG showed slow high-amplitude flashes with epileptic discharges and disorganised cortical rhythm; EMG was normal. Uncontrolled seizures made the child’s condition unstable and required palliative care. The authors could not determine whether this represented an undeclared molecular karyotype or a combination of PCH types 2A, 4 and 5.
No drug treatment, survival benefit, or response rate is reported in any of these abstracts. What is missing is any clinical trial testing a therapeutic intervention, any systematic patient stratification beyond genotype, and any funding for such trials. The natural history is well described genetically and neuroradiologically, but no modifiable target or treatment has been identified.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Brain · 2010 · 225 citations · open access
Clinical, neuroradiological and genetic findings in pontocerebellar hypoplasia
AbstractPontocerebellar hypoplasia is a group of autosomal recessive neurodegenerative disorders with prenatal onset. The common characteristics are cerebellar hypoplasia with variable atrophy of the cerebellum and the ventral pons. Supratentorial involvement is reflected by variable neocortical atrophy, ventriculomegaly and microcephaly. Mutations in the transfer RNA splicing endonuclease subunit genes (TSEN54, TSEN2, TSEN34) were found to be associated with pontocerebellar hypoplasia types 2 and 4. Mutations in the mitochondrial transfer RNA arginyl synthetase gene (RARS2) were associated with pontocerebellar hypoplasia type 6. We studied a cohort of 169 patients from 141 families for mutations in these genes, of whom 106 patients tested positive for mutations in one of the TSEN genes or the RARS2 gene. In order to delineate the neuroradiological and clinical phenotype of patients with mutations in these genes, we compared this group with 63 patients suspected of pontocerebellar hypoplasia who were negative on mutation analysis. We found a strong correlation (P < 0.0005) between TSEN54 mutations and a dragonfly-like cerebellar pattern on magnetic resonance imaging, in which the cerebellar hemispheres are flat and severely reduced in size and the vermis is relatively spared. Mutations in TSEN54 are clinically associated with dyskinesia and/or dystonia and variable degrees of spasticity, in some cases with pure generalized spasticity. Nonsense or splice site mutations in TSEN54 are associated with a more severe phenotype of more perinatal symptoms, ventilator dependency and early death. In addition, we present ten new mutations in TSEN54, TSEN2 and RARS2. Furthermore, we show that pontocerebellar hypoplasia type 1 together with elevated cerebrospinal fluid lactate may be caused by RARS2 mutations.
Journal of Child Neurology · 2013 · 19 citations · open access
Novel Mutations in <i>TSEN54</i> in Pontocerebellar Hypoplasia Type 2
AbstractPontocerebellar hypoplasias represent a group of neurodegenerative autosomal recessive disorders characterized by hypoplasia/atrophy of the cerebellum, hypoplastic ventral pons, and microcephaly and associated with various clinical features. Pontocerebellar hypolasia type 2 is the most common form, and different mutations in genes encoding subunits of the transfer ribonucleic acid (RNA)-splicing endonuclease (TSEN) complex were identified in patients. The authors report clinical, imaging, and molecular studies in 2 unrelated patients with different clinical pictures of the pontocerebellar hypoplasia type 2 spectrum and novel mutations in TSEN54, aiming to further define the clinical spectrum of the disease and possible indicators of more favorable progression. They identified a novel missense mutation c.355T>G/p.Y119D in compound heterozygosity with the "common" c.919G>T/p.A307S (patient 1) and a novel homozygous c.7ins6(CCGGAG)/p.E2-P3insPE variant (patient 2). An expanded array of mutations might contribute in defining possible differences in severity and phenotype-genotype correlations.
P95 The undeclared new type of pontocerebellar hypoplasia
Abstract<h3>Background</h3> Pontocerebellar hypoplasia (PCH) refers to a group of severe neurodegenerative disorders affecting growth and function of the brainstem and cerebellum, resulting in serious neurological consequences or psychomotor delay. Different types are classified according to the clinical picture and the spectrum of pathologic changes. <h3>Method</h3> Clinical, genetic, molecular, encephalographic, radiological, pathological and survival data were gathered. <h3>Results</h3> The patient report presents the medical history of a pontocerebellar hypoplasia (PCH) child, which unrepresented in previous case histories. Our patient has a heterozygote mutation in 8 exon gene TSEN54 and in 1 exon in gene EXOSC3. It is important to note that such a mutation in TSEN54, however, in different exons is presented in PCH type 2A, PCH type 4 and PCH type 5 and a mutation in gene EXOSC3 is demonstrated in PCH1B. We compared all known PCH types (19 PCH types) and tried to find correlations between this child’s features and those associated with the other one. This case tries to resolve the diagnostic issues related to the combination of features of these different types simultaneously in one child. Clinical features include seizures, feeding and swallowing disorders, strabismus, kyphoscoliosis, poor balance and coordination, mental retardation, severe speech impairment, hypotonia. Our patient had some phenotype peculiarities, such as: brachycephalia, protruding brow arcs, preauricular excrescence, medial eyebrow flare, hypoplasia of the lower face, large nose, eyelids ptosis. The morphological changes of this case were microgyria, pontocerebellar hypoplasia, and corpus colosum hypoplasia. Moreover, an MRI confirmed TH4 rachischisis, and an ultrasound revealed thymomegaly and septal defects. An EEG demonstrated slow flashes with high-amplitude. In the frontal leads we can see epileptic discharges and periods of disorganization of cortical rhythm. EMG results were normal. Blood test showed no abnormalities. Uncontrolled seizures made the child’s condition unstable and he needed palliative care. <h3>Conclusion</h3> Therefore, our investigation continues to determine whether the child has a pontocerebellar hypoplasia (PCH) with undeclared molecular karyotype or has a combination of PCH type 2A, PCH type 4 and PCH type 5.
Arquivos de Neuro-Psiquiatria · 2023 · 0 citations · open access
Case report: pontocerebellar hypoplasia type 1D
AbstractCase presentation: This report aims to describe the case of a patient with a rare diagnosis of type 1D pontocerebellar hypoplasia (PCH1D), resulting from the alteration of the EXOSC9 gene. G. T. S. D. S., male, 1 year and 2 months old, fruit of unplanned pregnancy of non-consanguineous parents. Prenatal care was complete. The patient was born by vaginal delivery without complications, with 36 weeks and 6 days of gestational age, and with the following measurements: height = 44.5 cm; weight = 2,660 kg; head circumference = 33.8 cm.
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.
