DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for pontocerebellar hypoplasia, type 16 — 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 modulePontocerebellar hypoplasia, type 16 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 pontocerebellar hypoplasia, type 16 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.
What the evidence adds up to
Pontocerebellar hypoplasia type 16 is an autosomal recessive neurodegenerative disorder with prenatal onset. The common characteristics across the pontocerebellar hypoplasia group are cerebellar hypoplasia with variable atrophy of the cerebellum and ventral pons, plus supratentorial involvement reflected by variable 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; 63 patients suspected of having pontocerebellar hypoplasia were negative on mutation analysis. A strong correlation (P < 0.0005) 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. TSEN54 mutations are clinically associated with dyskinesia or dystonia and variable spasticity, sometimes pure generalised spasticity; nonsense or splice site mutations in TSEN54 produce a more severe phenotype with perinatal symptoms, ventilator dependency and early death.
Pontocerebellar hypoplasia type 1 is characterised by hypoplasia of the pons and cerebellum with degeneration of motor neurons in the anterior horn of the spinal cord. One reported case involved a 4-year-old female with severe psychomotor retardation, microcephaly, generalised hypotonia, muscle hypotrophy, limb contractions, absent stretch reflex and neonatal-onset epilepsy. MRI showed pontocerebellar hypoplasia; electroneuromyography indicated axonal neuropathy and deltoid muscle biopsy showed neurogenic muscular atrophy. In mitochondrial respiratory chain studies of muscle homogenate and skin fibroblasts, complex IV values were at the lower limits of normal. Genetic testing for spinal muscular atrophy was negative. The authors note that mitochondrial respiratory chain studies may be of interest in pontocerebellar hypoplasia to explain the disorder's mechanism.
Classification based on clinical, imaging and neuropathological findings does not differentiate between pontocerebellar hypoplasia subtypes with different genetic causes. Not all cases of clinically defined pontocerebellar hypoplasia type 4 result from TSEN54 mutations. Several genes known to be important for cerebellar development have been excluded as causes of pontocerebellar hypoplasia types 4 and 5. Two clinically diagnosed cases of pontocerebellar hypoplasia type 2 from two Portuguese families presented neurological involvement from birth, progressive microcephaly, chorea, dystonia, myoclonic jerks, pontocerebellar hypoplasia and progressive cerebral cortical atrophy; one child had consanguineous parents.
What remains missing is any specific treatment or drug therapy tested in these patients. No clinical trial data exist for pontocerebellar hypoplasia type 16. The field lacks prospective natural history studies, validated biomarkers, and patient stratification by genotype. Funding for systematic drug screening or repurposing studies in this ultra-rare condition is 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.
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.
Pontocerebellar Hypoplasia: Review of Classification and Genetics, and Exclusion of Several Genes Known to Be Important for Cerebellar Development
AbstractThe pontocerebellar hypoplasias are a heterogeneous group of rare and devastating conditions characterized by multiple structural abnormalities of the ventral pons, inferior olive, and cerebellum. Here, we briefly review these conditions and discuss genes recently discovered to be involved in pontocerebellar hypoplasia pathogenesis. We then present data that exclude several genes important for cerebellar development as causes of pontocerebellar hypoplasia-4 and pontocerebellar hypoplasia-5, and we demonstrate that not all cases of clinically defined pontocerebellar hypoplasia-4 result from mutations in TSEN54. We conclude that classification based on clinical, imaging, and neuropathological findings does not differentiate between pontocerebellar hypoplasia subtypes with different genetic causes.
Developmental Medicine & Child Neurology · 1997 · 10 citations · open access
Pontocerebellar hypoplasia with microcephaly and dyskinesia: report of two cases
AbstractWe present two clinically diagnosed cases of pontocerebellar hypoplasia with microcephaly and dyskinesia (pontocerebellar hypoplasia type 2) from two different Portuguese families. Both children presented neurological involvement from birth, progressive microcephaly, exuberant chorea and dystonia, myoclonic jerks, pontocerebellar hypoplasia, and progressive cerebral cortical atrophy. One child had consanguineous parents.
Hipoplasia pontocerebelosa tipo 1: aportación de un caso
AbstractINTRODUCTION: Pontocerebellar hypoplasias constitute a group of hereditary neurodegenerative disorders of uncertain aetiopathogenesis. They have been reported as being associated with deficiencies of complexes in the mitochondrial respiratory chain (MRC) and with congenital disorders of glycosylation. On the basis of clinical and neuropathological criteria, two phenotypes can be distinguished in this condition. Pontocerebellar hypoplasia type 1 is characterised by hypoplasia of the pons and the cerebellum associated with the degeneration of the motor neurons in the anterior horn of the spinal cord. CASE REPORT: A 4-year-old female with symptoms of severe psychomotor retardation associated with microcephaly, important generalised hypotonia, muscle hypotrophy, contractions in the four limbs, absence of stretch reflex and epilepsy with onset in the neonatal period. Magnetic resonance imaging of the brain revealed pontocerebellar hypoplasia. An electroneuromyography showed a trace that was compatible with axonal neuropathy and a biopsy of the deltoid muscle revealed the existence of neurogenic muscular atrophy. In the MRC study conducted in muscle homogenate and in skin fibroblasts, complex IV values were found to be at the lower limits of what could be considered to be normal levels. Results of the genetic study for spinal muscular atrophy were negative. CONCLUSIONS: The case reported here could be included as a case of pontocerebellar hypoplasia type 1. MRC studies can be of interest in cases of pontocerebellar hypoplasia in order to explain the role it plays in this disorder.
Zurich Open Repository and Archive (University of Zurich) · 2011 · 0 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.
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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