DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for episodic ataxia type 1 — 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 1 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 1 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 1981 double-blind, triple-crossover trial of low-dose oral physostigmine in 21 patients with various inherited ataxias found the drug more effective than placebo overall (p < 0.05). Thirteen patients had consistent, statistically significant responses to physostigmine; 8 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. A 1997 double-blind crossover study using a transdermal physostigmine patch (releasing about 6 mg over 24 hours) in 19 patients with degenerative cerebellar diseases (11 autosomal dominant, 8 idiopathic) found no significant effect on cerebellar symptoms, concluding that treatment with physostigmine does not improve the conditions of patients with ataxia.
A 2009 review of symptomatic treatment for ataxia states that "the cupboard is bare." It reports an apparent success with varenicline, given initially for smoking cessation to a 64-year-old man with fragile X tremor/ataxia syndrome (FXTAS) who had 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 one week, he noted a striking improvement. No controlled trial data for varenicline in episodic ataxia type 1 are provided in these abstracts.
A 2018 study identified a biallelic 3-bp deletion (p.K19del) in the CHP1 gene in two siblings from a consanguineous family with complex autosomal recessive cerebellar ataxia. The mutation caused mutant CHP1 to fail to integrate into functional protein complexes and to aggregate, leading to reduced soluble CHP1 and diminished membrane targeting of NHE1, a sodium/hydrogen exchanger implicated in syndromic ataxia-deafness. A zebrafish model of Chp1 deficiency showed movement defects, cerebellar hypoplasia, and motor axon abnormalities, which were ameliorated by coinjection with wild-type human CHP1 mRNA but not mutant mRNA. No focused screening of 976 additional ataxia patients (ARCA cohort N=319, NeurOmics cohort N=657) or GeneMatcher yielded further CHP1 variants, indicating the scarcity of such mutations.
No abstract in this set reports a controlled trial specifically for episodic ataxia type 1. The 1981 physostigmine trial included various inherited ataxias but did not specify episodic ataxia type 1 as a subgroup. The 1997 trial excluded episodic ataxias. The 2018 CHP1 mutation study describes a recessive ataxia, not episodic ataxia type 1. What is missing for episodic ataxia type 1 specifically is any randomised controlled trial data for any drug, any validated biomarker for stratifying patients by genotype, and dedicated funding for a trial that recruits patients by confirmed KCNA1 mutation rather than by clinical syndrome alone.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
British Medical Bulletin · 2017 · 215 citations · open access
Friedreich’s ataxia: clinical features, pathogenesis and management
AbstractINTRODUCTION: Friedreich's ataxia is the most common inherited ataxia. SOURCES OF DATA: Literature search using PubMed with keywords Friedreich's ataxia together with published papers known to the authors. AREAS OF AGREEMENT: The last decade has seen important advances in our understanding of the pathogenesis of disease. In particular, the genetic and epigenetic mechanisms underlying the disease now offer promising novel therapeutic targets. AREAS OF CONTROVERSY: The search for effective disease-modifying agents continues. It remains to be determined whether the most effective approach to treatment lies with increasing frataxin protein levels or addressing the metabolic consequences of the disease, for example with antioxidants. AREAS TIMELY FOR DEVELOPING RESEARCH: Management of Freidreich's ataxia is currently focussed on symptomatic management, delivered by the multidisciplinary team. Phase II clinical trials in agents that address the abberrant silencing of the frataxin gene need to be translated into large placebo-controlled Phase III trials to help establish their therapeutic potential.
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.
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.
Neurology Genetics · 2018 · 24 citations · open access
Biallelic CHP1 mutation causes human autosomal recessive ataxia by impairing NHE1 function
Abstract<h3>Objective:</h3> To ascertain the genetic and functional basis of complex autosomal recessive cerebellar ataxia (ARCA) presented by 2 siblings of a consanguineous family characterized by motor neuropathy, cerebellar atrophy, spastic paraparesis, intellectual disability, and slow ocular saccades. <h3>Methods:</h3> Combined whole-genome linkage analysis, whole-exome sequencing, and focused screening for identification of potential causative genes were performed. Assessment of the functional consequences of the mutation on protein function via subcellular fractionation, size-exclusion chromatography, and fluorescence microscopy were done. A zebrafish model, using Morpholinos, was generated to study the pathogenic effect of the mutation in vivo. <h3>Results:</h3> We identified a biallelic 3-bp deletion (p.K19del) in <i>CHP1</i> that cosegregates with the disease. Neither focused screening for <i>CHP1</i> variants in 2 cohorts (ARCA: N = 319 and NeurOmics: N = 657) nor interrogating GeneMatcher yielded additional variants, thus revealing the scarcity of <i>CHP1</i> mutations. We show that mutant CHP1 fails to integrate into functional protein complexes and is prone to aggregation, thereby leading to diminished levels of soluble CHP1 and reduced membrane targeting of NHE1, a major Na<sup>+</sup>/H<sup>+</sup> exchanger implicated in syndromic ataxia-deafness. Chp1 deficiency in zebrafish, resembling the affected individuals, led to movement defects, cerebellar hypoplasia, and motor axon abnormalities, which were ameliorated by coinjection with wild-type, but not mutant, human <i>CHP1</i> messenger RNA. <h3>Conclusions:</h3> Collectively, our results identified <i>CHP1</i> as a novel ataxia-causative gene in humans, further expanding the spectrum of ARCA-associated loci, and corroborated the crucial role of NHE1 within the pathogenesis of these disorders.
Revista médica de Chile · 2018 · 6 citations · open access
Características clínicas de 63 pacientes con ataxia
AbstractBACKGROUND: Ataxia can be classified as genetic, sporadic or acquired. AIM: To report the clinical features of a group of patients with ataxia. MATERIAL AND METHODS: Review of medical records of patients consulting in a specialized center in movement disorders. Those records in which the diagnosis of "ataxia" or "ataxic syndrome" appeared, were selected for the review. RESULTS: Of 4,282 records surveyed, the diagnosis of ataxia appeared in 95. After eliminating repeated or incomplete records, 63 were reviewed. RESULTS: Ataxia was sporadic, genetic and acquired in 27, 22 and 14 patients, respectively. The mean age at presentation for genetic, acquired and sporadic ataxia was 24, 46 and 53 years respectively. All autosomal dominant ataxias were type 3 spinocerebellar ataxia (SCA). Friedrich's ataxia was the most common recessive form. Most sporadic forms of ataxia were multiple system atrophy with predominant cerebellar ataxia (MSA-C) subtype. CONCLUSIONS: Considering the heterogeneity of patients with ataxia, we propose a method to approach them.
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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