DeCure for Autosomal recessive spinocerebellar ataxia 17
DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for autosomal recessive spinocerebellar ataxia 17 — 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 moduleAutosomal recessive spinocerebellar ataxia 17 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 autosomal recessive spinocerebellar ataxia 17 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
In a 2004 report of a single homozygous SCA17 patient with 48 glutamines, age at onset was not lower than in heterozygotes with the same repeat size, but the clinical course was rapidly progressive dementia and chorea. Neuronal loss was most prominent in the Purkinje cell layer and striatum, while intranuclear polyglutamine accumulation was widespread, especially in cerebral cortex and striatum. A 2004 study of a four-generation family with 16 affected patients carrying a stable 52 CAG repeat expansion found that behavioural symptoms and frontal impairment dominated early stages, preceding ataxia, rigidity, and dystonic movements. Neuropathology showed cortical, subcortical and cerebellar atrophy, Purkinje cell loss, pseudohypertrophic degeneration of the inferior olive, and marked neuronal loss in the caudate nucleus and medial thalamic nuclei, together with neuronal intranuclear inclusions. The authors concluded that initial presenile dementia with behavioural symptoms should be added to the more commonly recognised ataxia, rigidity, and dystonic movements.
A 2011 review notes that over 35 genetic subtypes of dominant ataxia exist, with CAG repeat expansions still the more common cause, and that repeat length partially explains age at onset, disease severity, progression, and core phenotype. The review states that despite progress in molecular genetics and suggested pathways—including misfolding and aggregation, impairment of protein quality control, abnormal protein interactions, disruption of gene transcription, RNA toxicity, and changes in glutamate and calcium signalling—there is still no drug specifically designed for or targeted at the mechanisms at play.
In 2012, transgenic mice expressing mutant human TBP under a Purkinje-cell-specific promoter developed ataxia within 2–5 months, showed reduced fall latency on rotarod, and displayed Purkinje cell degeneration, reactive gliosis, and neuroinflammation. These mice were used to test granulocyte-colony stimulating factor, which the authors report had a neuroprotective effect, ameliorating neurological and behavioural deficits. No human trial of this agent in SCA17 is described in these abstracts.
What remains missing is any drug approved or in clinical trials for SCA17 in humans. The transgenic mouse work with granulocyte-colony stimulating factor has not been followed by human studies. No trial design, patient stratification strategy, or funding for a clinical trial is reported in these abstracts.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
AbstractWe report a homozygous case of spinocerebellar ataxia type 17 with 48 glutamines. The age of the patient at disease onset was not lower than those of heterozygotes with the same CAG-repeat sizes, but the clinical manifestations were rapidly progressive dementia and chorea. Neuronal loss was relatively restricted and most prominent in the Purkinje cell layer and striatum; however, intranuclear neuronal polyglutamine accumulation was widespread, with a high frequency in the cerebral cortex and striatum.
Behavioral Disorder, Dementia, Ataxia, and Rigidity in a Large Family With TATA Box-Binding Protein Mutation
AbstractBACKGROUND: Spinocerebellar ataxia type 17 is an autosomal dominant cerebellar ataxia caused by a CAG repeat expansion in the TATA box-binding protein gene. Ataxia is typically the first sign whereas behavioral symptoms occur later. OBJECTIVE: To characterize the unusual phenotypic expression of a large spinocerebellar ataxia type 17 kindred. DESIGN: Clinical, neuropathological, and molecular genetic characterization of a 4-generation family with 16 affected patients. RESULTS: Behavioral symptoms and frontal impairment dominated the early stages preceding ataxia, rigidity, and dystonic movements. Neuropathological examination showed cortical, subcortical, and cerebellar atrophy. Purkinje cell loss and gliosis, pseudohypertrophic degeneration of the inferior olive, marked neuronal loss and gliosis in the caudate nucleus, and in the medial thalamic nuclei were salient features together with neuronal intranuclear inclusions stained with anti-TATA box-binding protein and antipolyglutamine antibodies. The disease was caused by a stable 52 CAG repeat expansion of the TATA box-binding protein gene, although there was apparent variability in the age of onset. CONCLUSION: The characteristics of this family broaden the clinical picture of spinocerebellar ataxia type 17: initial presenile dementia with behavioral symptoms should be added to ataxia, rigidity, and dystonic movements, which are more commonly encountered.
AbstractThe relevant clinical, genetic, and cell biologic aspects of the dominantly inherited spinocerebellar ataxias (SCAs) are reviewed in this article. SCAs are diseases of the entire nervous system; in addition to cerebellar ataxia, the central (but not obligate) disease feature, many noncerebellar complications can be present as well. There are over 35 genetic subtypes: although those caused by expanded CAG repeats are still the more common ones, the majority of the recent SCAs have been caused by more conventional mutations. Genotype-phenotype correlations do exist and are most clear for the repeat expansion, where repeat length partially explains age at onset, disease severity and progression, and the core clinical phenotype. Some common themes within the disease mechanisms seem to emerge, including misfolding and aggregation, impairment of the protein quality control system, abnormal protein interactions, disruption of gene transcription, RNA toxicity, and changes in glutamate and calcium signaling. Yet despite this exciting progress in the molecular genetic background and suggested corresponding pathways, there is still no drug available that is specifically designed for or targeted at the mechanisms at play.
Journal of Neurochemistry · 2012 · 0 citations · open access
Determinação experimental e numérica das curvas de funcionamento de bombas centrífugas
AbstractSpinocerebellar ataxia type 17 (SCA17) is an autosomal dominant inherited disorder characterized by degeneration of spinocerebellar tracts and selected brainstem neurons owing to the expansion of a CAG repeat of the human TATA-binding protein (hTBP) gene. To gain insight into the pathogenesis of this hTBP mutation, we generated transgenic mice with the mutant hTBP gene driven by the Purkinje specific protein (Pcp2/L7) gene promoter. Mice with the expanded hTBP allele developed ataxia within 2-5 months. Behavioral analysis of L7-hTBP transgenic mice showed reduced fall latency in a rotarod assay. Purkinje cell degeneration was identified by immunostaining of calbindin and IP3R1. Reactive gliosis and neuroinflammation occurred in the transgenic cerebellum, accompanied by up-regulation of GFAP and Iba1. The L7-hTBP transgenic mice were thus confirmed to recapitulate the SCA17 phenotype and were used as a disease model to explore the potential of granulocyte-colony stimulating factor in SCA17 treatment. Our results suggest that granulocyte-colony stimulating factor has a neuroprotective effect in these transgenic mice, ameliorating their neurological and behavioral deficits. These data indicate that the expression of the mutant hTBP in Purkinje cells is sufficient to produce cell degeneration and an ataxia phenotype, and constitutes a good model for better analysis of the neurodegeneration in SCA17.
Advance in Molecular Genetics on Spinocerebellar Ataxia
AbstractSpinocerebellar ataxia is a group of autosomal dominant and heterogeneous neurodegenerative disease. Different genetic mutation may cause different subtypes of spinocerbellar ataxia. Up to now, with the rapid development of molecular genetic study, nearly 30 mutated genes associated with various subtypes of spinocerebella ataxias have been located and some of them have been identified. Most of the mutated genes are caused by the abnormal expansion of trinucleotide. In this review, the clinical and genetic features of the recently identified spinocerebellar ataxias will be described.
Key words:
Spinocerebellar ataxia ; Trinucleotide repeated expansion ; Molecular genetics ;
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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