DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for episodic ataxia type 2 — 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 2 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 2 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 voltage-gated channel subunit alpha1 A (CACNA1A) — CACNA1A 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 clrdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8X93 · 2.92 Å · ligand CHOLESTEROL (CLR). Experimental structure, not a prediction.
What the evidence adds up to
A 2005 genome-wide screen for episodic ataxia in a large pedigree was published, but the abstract of that paper actually describes a study of midbody proteins during cell division and contains no information about ataxia genetics or any drug. The 2009 review of cerebellar ataxias notes that therapeutic agents under investigation are targeted to deleterious pathways, but gives no specific drug names or trial results for episodic ataxia type 2.
Two controlled trials of physostigmine in inherited ataxias exist, but neither is specific to episodic ataxia type 2. A 1981 double-blind, triple-crossover trial gave 21 patients with various inherited ataxias low oral doses of physostigmine or placebo for 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. Only three patients improved on placebo. Responses did not correlate with age, sex, or severity of ataxia. A 1997 double-blind crossover study gave 19 patients with degenerative cerebellar diseases (11 with autosomal dominant cerebellar ataxia, 8 with idiopathic cerebellar ataxia) a transdermal physostigmine patch releasing about 6 mg over 24 hours or placebo for four weeks each. Physostigmine patches had no significant effect on cerebellar symptoms. The authors concluded that treatment with physostigmine does not improve the conditions of patients with ataxia.
A 2011 review of clinical challenges in the ataxias states that ataxias are rare, that etiologic heterogeneity makes individual entities even rarer, and that substantial numbers of patients remain poorly understood. It notes that available assessment techniques require large numbers of patients for clinical trials and that cooperative efforts, better assessment tools, and novel trial designs are needed. It adds that opportunities exist for targeting at-risk individuals for effective therapies but that how this can be done is not clear.
What is still missing for episodic ataxia type 2 specifically: no controlled trial of any drug has been published in patients with a confirmed genetic diagnosis of episodic ataxia type 2. The physostigmine trials enrolled mixed ataxia populations and gave contradictory results. No trial has tested a drug targeted to the known pathogenic mechanism (KCNA1 potassium channel dysfunction). Patient numbers are too small for conventional trial designs, and no validated biomarker or sensitive, specific outcome measure for episodic attacks exists. Funding for a genetically stratified, placebo-controlled trial of a potassium channel modulator remains 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.
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.
A genome-wide screen and linkage mapping for a large pedigree with episodic ataxia
Abstract<h3>Abstract</h3> The midbody is an organelle that forms between the two daughter cells during cytokinesis. It co-ordinates the abscission of the nascent daughter cells and is composed of a multitude of proteins that are meticulously arranged into distinct temporal and spatial localization patterns. However, very little is known about the mechanisms that regulate the localization and function of midbody proteins. Here, we analyzed the temporal and spatial profiles of key midbody proteins during mitotic exit under normal conditions and after treatment with drugs that affect phosphorylation and proteasome-mediated degradation to decipher the impacts of post-translational modifications on midbody protein dynamics. Our results highlighted that midbody proteins show distinct spatio-temporal dynamics during mitotic exit and cytokinesis that depend on both ubiquitin-mediated proteasome degradation and phosphorylation/de-phosphorylation. They also identified two discrete classes of midbody proteins: ‘transient’ midbody proteins -including Anillin and PRC1-which rapidly accumulate at the midbody after anaphase onset and then slowly disappear, and ‘stable’ midbody proteins -including CIT-K, KIF14 and KI1F20A-which instead persist at the midbody throughout cytokinesis and also post abscission. These two classes of midbody proteins display distinct interaction networks with ubiquitylation factors, which could potentially explain their different dynamics and stability during cytokinesis.
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
Double-blind Crossover Study With Physostigmine in Patients With Degenerative Cerebellar Diseases
AbstractOBJECTIVE: To determine whether treatment with physostigmine can improve the conditions of patients with ataxia. DESIGN: A double-blind crossover study with physostigmine was performed in 19 patients with degenerative cerebellar diseases. SETTING: Patients were selected from an ongoing prospective follow-up study at the university hospital in Lübeck, Germany. PATIENTS: Eleven patients with autosomal dominant cerebellar ataxia and 8 patients with idiopathic cerebellar ataxia. INTERVENTION: Physostigmine was administered by using a transdermal system (patch) containing 30 mg of physostigmine as a base, of which about 6 mg is released during 24 hours along a diffusion gradient. Each treatment phase with the physostigmine patch or the placebo lasted 4 weeks, after which the treatment of patients was crossed over to the other phase. MAIN OUTCOME MEASURES: Ataxia was documented and quantified by using a clinical score and posturographic measures. RESULTS: Physostigmine patches had no significant effect on cerebellar symptoms. CONCLUSION: Treatment with physostigmine does not improve the conditions of patients with ataxia.
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.
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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