DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for episodic ataxia type 8 — 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 moduleEpisodic ataxia type 8 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 episodic ataxia type 8 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
ubiquitin protein ligase E3 component n-recognin 4 (UBR4) — UBR4 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 apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9QWS · 3.1 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
In a 2001 Italian genetic study of 167 ataxic patients, five were found to carry abnormally expanded CTA/CTG repeats associated with spinocerebellar ataxia type 8 (SCA8). Three of those five had pure cerebellar ataxia; one had vitamin E deficiency and one had gluten ataxia. No expanded alleles were found in 161 healthy controls or 125 psychiatric patients. The authors concluded that CTG expansions may be linked to SCA8 but noted that unknown additional factors could predispose to the disease. This study did not test any drug.
A 1981 double-blind, triple-crossover trial tested low-dose oral physostigmine against placebo in 21 patients with various inherited ataxias over four sequential three-month periods. Overall, the drug was more effective than placebo (p < 0.05). Thirteen patients had consistent, statistically significant responses to physostigmine; eight did not (χ² = 46.9, p < 0.0001). Only three patients improved on placebo. Responses did not correlate with age, sex, or severity of ataxia, and different aspects of ataxia improved in different patients. This trial did not specifically study episodic ataxia type 8.
A 2011 review of clinical challenges in the ataxias noted that these are rare diseases with substantial numbers of patients still poorly understood. The authors stated that available assessment techniques require large numbers of patients for clinical trials and called for cooperative efforts, better assessment tools, and novel trial designs. They noted that opportunities exist for targeting at-risk individuals but that how this can be done is not clear.
A 2007 review of primary episodic ataxias covered clinical and genetic diagnosis, genotype-phenotype correlations, pathophysiology, and treatment, but the abstract provided no specific drug trial results or efficacy data for episodic ataxia type 8. What is still missing for episodic ataxia type 8 specifically is any dedicated, adequately powered clinical trial, validated outcome measures for this ultra-rare subtype, and a clear understanding of which patients might respond to which intervention.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Current Opinion in Neurology · 2009 · 187 citations
Cerebellar ataxias
AbstractPURPOSE OF REVIEW: The term 'cerebellar ataxias' encompasses the various cerebellar disorders encountered during daily practice. Patients exhibit a cerebellar syndrome and can also present with pigmentary retinopathy, extrapyramidal movement disorders, pyramidal signs, cortical symptoms (seizures, cognitive impairment/behavioural symptoms), and peripheral neuropathy. The clinical diagnosis of subtypes of ataxias is complicated by the salient overlap of the phenotypes between genetic subtypes. The identification of the causative mutations of many hereditary ataxias and the development of relevant animal models bring hope for effective therapies in neurodegenerative ataxias. RECENT FINDINGS: We describe the current classification of cerebellar ataxias and underline the recent discoveries in molecular pathogenesis. Cerebellar disorders can be divided into sporadic forms and inherited diseases. Inherited ataxias include autosomal recessive cerebellar ataxias, autosomal dominant cerebellar ataxias/spinocerebellar ataxia) and episodic ataxias, and X-linked ataxias. From a motor control point of view, the leading theories of ataxia are based on neural representations or 'internal models' to emulate fundamental natural processes such as body motion. SUMMARY: Recent molecular advances have direct implications for research and daily practice. We provide a framework for the diagnosis of ataxias. For the first time, the therapeutic agents under investigation are targeted to deleterious pathways.
Genetic and Clinical Analysis of Spinocerebellar Ataxia Type 8 Repeat Expansion in Italy
AbstractBACKGROUND: The spinocerebellar ataxias (SCAs) are clinically heterogeneous disorders caused by triplet repeat expansions in the sequence of specific disease genes. Spinocerebellar ataxia type 8 (SCA8), originally described in a family characterized by pure cerebellar ataxia with slow disease progression, presents with expansion of combined CTA/CTG repeats. OBJECTIVE: To perform SCA8 repeat expansion analysis in a heterogeneous group of ataxic patients, to determine the prevalence of this mutation in our patients and establish the frequency of expanded CTA/CTG repeats in a large group of control subjects. PATIENTS: One hundred sixty-seven patients affected by sporadic, autosomal dominant and recessive hereditary ataxia were clinically examined and analyzed for SCA8 expansion. We further studied 161 control subjects and 125 patients with psychiatric disorders. RESULTS: We found abnormally expanded CTA/CTG repeats in 5 ataxic patients, 3 of them characterized by pure cerebellar ataxia. One patient had vitamin E deficiency and 1 patient with a sporadic case was affected by gluten ataxia. No evidence of expanded alleles was found in healthy control subjects and in patients with psychiatric disorders. CONCLUSIONS: Our data support the evidence that CTG expansions may be linked to SCA8, since the pathogenic expansions have been found only among patients with genetically unidentified forms of hereditary and sporadic ataxia. Patients carrying expanded alleles present peculiar phenotypic features, thus suggesting that unknown additional factors could probably predispose to the disease.
Double‐blind, triple‐crossover trial of low doses of oral physostigmine in inherited ataxias
AbstractThe signs of ataxia in patients with inherited ataxias have been reported to improve after single injections or single oral doses of physostigmine. To study this effect, 21 patients with various inherited ataxias underwent a randomized, double-blind, triple-crossover trial of physostigmine and inert placebo taken orally in low doses for four sequential 3-month periods. Overall, the drug was more effective than the placebo (<i>p</i> <0.051. Thirteen patients had consistent, statistically significant responses to physostigmine; 8 did not (x<sup>2</sup>=46.9, <i>p</i> <0.0001). Only three patients improved on placebo. Responses did not correlate with age, sex, or severity of ataxia. Some aspects of ataxia improved in some patients, other aspects in other patients. Preliminary accounts of this work were previously reported.1-2
AbstractAtaxias are rare diseases and the etiologic heterogeneity make individual entities even rarer. There are still substantial numbers of patients who are still poorly understood. Available assessment techniques still point to large numbers of patients needed for clinical trials and the need for cooperative efforts, better assessment tools and novel trial designs. Better understanding of neural circuitry abnormalities may lead to more effective symptomatic therapy. Opportunities exist for targeting at risk individuals for effective therapies but how this can be done is not clear. Preventive strategies may become feasible in many ataxias.
Galter Health Sciences Library, Northwestern University · 2007 · 0 citations · open access
Primary Episodic Ataxias
AbstractThe clinical and genetic diagnosis, genotype-phenotype correlations, pathophysiology and treatment of primary episodic ataxia syndromes are reviewed by researchers from Departments of Neurology, UCLA School of Medicine, Los Angeles, CA; National Hospital for Neurology, Queen Square, London, UK; Johns Hopkins University School of Medicine, Baltimore, MD; and University of Rochester School of Medicine, NY, USA.
AbstractThe cupboard is bare when it comes to the symptomatic treatment of ataxia. These authors report apparent success with varenicline, initially given for smoking cessation to a 64-year-old man with prominent ataxia due to fragile X tremor/ataxia syndrome (FXTAS), a 9-year history of tremor, and a 4-year history of gait ataxia with falling. After taking 1 mg of varenicline twice daily for 1 week, he noted a striking …
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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