DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for episodic ataxia type 5 — 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 5 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 5 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
A 2011 randomised, double-blind, crossover trial of 4-aminopyridine (4AP) in 10 subjects with familial episodic ataxia with nystagmus, seven of whom had genetically confirmed episodic ataxia type 2 (EA2), found that 4AP reduced attack frequency. Patients on placebo had a median of 6.50 attacks per month; those on 4AP (5 mg three times daily) had a median of 1.65 attacks per month (p = 0.03). Median monthly attack duration fell from 13.65 hours on placebo to 4.45 hours on 4AP (p = 0.08). The Vestibular Disorders Activities of Daily Living Scale score decreased from 6.00 to 1.50 (p = 0.02). The trial provided Class II evidence that 4AP decreases attack frequency and improves patient-reported quality of life.
Two trials of physostigmine in inherited ataxias gave contradictory results. A 1981 double-blind, triple-crossover trial of low-dose oral physostigmine in 21 patients with various inherited ataxias reported that the drug was more effective than placebo overall (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. However, a 1997 double-blind crossover study of transdermal physostigmine patches in 19 patients with degenerative cerebellar diseases (11 with autosomal dominant cerebellar ataxia, 8 with idiopathic cerebellar ataxia) found no significant effect on cerebellar symptoms.
A 2005 abstract on a genome-wide screen and linkage mapping for a large pedigree with episodic ataxia is not relevant to treatment; it describes a study of midbody protein dynamics during cytokinesis. Two 2007 review articles on primary episodic ataxia syndromes are cited but provide no new trial data.
What is still missing is a larger, adequately powered trial of 4-aminopyridine specifically in genetically confirmed episodic ataxia type 5, as the existing trial was small and focused on EA2. No trial has tested any drug in a cohort defined by the CACNA1A mutation that causes EA5. Funding for such a trial, and for the genetic screening needed to identify and stratify patients, 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.
Neurology · 2011 · 208 citations · open access
A randomized trial of 4-aminopyridine in EA2 and related familial episodic ataxias
AbstractOBJECTIVE: The therapeutic effects of 4-aminopyridine (4AP) were investigated in a randomized, double-blind, crossover trial in 10 subjects with familial episodic ataxia with nystagmus. METHODS: After randomization, placebo or 4AP (5 mg 3 times daily) was administered for 2 3-month-long treatment periods separated by a 1-month-long washout period. The primary outcome measure was the number of ataxia attacks per month; the secondary outcome measures were the attack duration and patient-reported quality of life (Vestibular Disorders Activities of Daily Living Scale [VDADL]). Nonparametric tests and a random-effects model were used for statistical analysis. RESULTS: The diagnosis of episodic ataxia type 2 (EA2) was genetically confirmed in 7 subjects. Patients receiving placebo had a median monthly attack frequency of 6.50, whereas patients taking 4AP had a frequency of 1.65 (p = 0.03). Median monthly attack duration decreased from 13.65 hours with placebo to 4.45 hours with 4AP (p = 0.08). The VDADL score decreased from 6.00 to 1.50 (p = 0.02). 4AP was well-tolerated. CONCLUSIONS: This controlled trial on EA2 and familial episodic ataxia with nystagmus demonstrated that 4AP decreases attack frequency and improves quality of life. LEVEL OF EVIDENCE: This crossover study provides Class II evidence that 4AP decreases attack frequency and improves the patient-reported quality of life in patients with episodic ataxia and related familial ataxias.
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.
American Journal of Health-System Pharmacy · 2009 · 22 citations
Amiodarone-induced neurotoxicity
AbstractPURPOSE: A case of amiodarone-induced neurotoxicity is reported. SUMMARY: A 76-year-old man arrived at the emergency department with complaints of increasing imbalance over the past 2.5 months after a recent discharge from the hospital. He reported that his balance had worsened over the past week and that he now must use a cane to walk. His medical history included coronary artery disease, peripheral vascular disease, hypertension, hyperlipidemia, and paroxysmal atrial fibrillation. Home medications included enteric-coated aspirin 325 mg orally daily, isosorbide dinitrate 20 mg orally twice daily, amiodarone hydrochloride 400 mg orally three times daily, hydralazine hydrochloride 10 mg orally four times daily, extended-release metoprolol succinate 142.5 mg (equivalent to metoprolol tartrate 150 mg) orally daily, simvastatin 80 mg orally daily, and warfarin sodium 2.5 mg orally daily. Physical examination of the patient revealed finger-to-nose dysmetria, unsteady gait with leftward prevalence, positive Romberg's sign, and inability to perform heel-to-toe walk. All radiographic imaging studies and laboratory test values ruled out acute pathologies, bleeding, masses, and ischemia. As there were no physiological findings for the patient's symptoms and after careful evaluation of the patient's drug regimen, the patient's amiodarone was discontinued. His ataxia began to slowly improve. All neurologic symptoms resolved completely five months after discontinuation of amiodarone. CONCLUSION: A 76-year-old man developed ataxia after taking amiodarone hydrochloride 400 mg orally three times daily for more than two months; the regimen was the intended loading dosage. The ataxia lessened over the first two weeks after the amiodarone was discontinued and resolved completely within five months after drug discontinuation.
Psychiatry and Clinical Neurosciences · 2002 · 15 citations · open access
Beneficial effects of tandospirone on ataxia of a patient with Machado‐Joseph disease
AbstractTandospirone citrate (tandospirone) is an anti-anxiety drug that acts by combining with serotonin receptor (5-hydroxytryptamine-1 A [5-HT1A]). Recently, there have been a few reports of its potential role in the treatment of cerebellar ataxia. We report the first case of a patient with Machado-Joseph disease in which we successfully treated cerebellar ataxia. In addition, his leg pain, insomnia, anorexia, and depression, which are thought to be related to 5-HT1A receptors, were also remarkably alleviated by treatment with tandospirone.
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 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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