DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for spastic ataxia 4 — 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 moduleSpastic ataxia 4 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 spastic ataxia 4 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
mitochondrial poly(A) polymerase (MTPAP) — MTPAP 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 3PQ1 · 3.1 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
A double-blind crossover study with 19 patients (11 autosomal dominant cerebellar ataxia, 8 idiopathic cerebellar ataxia) tested transdermal physostigmine patches releasing about 6 mg over 24 hours against placebo, each phase lasting 4 weeks. Clinical scores and posturographic measures showed no significant effect on cerebellar symptoms. The authors concluded that physostigmine does not improve ataxia.
Spastic ataxia 4 is a rare neurodegenerative disease with mixed ataxia and spasticity. A 2020 study analysed publicly available gene expression datasets from diseases presenting with ataxia or spasticity, focusing on a Cypriot family with a GBA2 missense variant (c.1780G>C, p.Asp594His) that causes spastic ataxia. The analysis found consistent differential expression of genes in sphingolipid pathways, and enrichment analysis pointed to PI3K-Akt signalling, MAPK signalling, calcium signalling, and lipid and carbohydrate metabolism as the most enriched pathways for ataxia and spasticity phenotypes. The pathogenetic mechanisms for most spastic ataxias remain unclear.
A 2014 review of 33 clinical trials for Friedreich ataxia compiled the most commonly used primary and secondary outcome measures, including rating scales, physical activity tests, biomarkers, and cardiac function assessments (left ventricular wall mass, systolic and diastolic function, echocardiography, immunogenicity). The review also discussed inclusion and exclusion criteria and genetic predisposition via epigenetics. No treatment efficacy data from those trials were reported in the abstract.
What is still missing: a specific clinical trial for spastic ataxia 4, any drug tested in that patient population, validated outcome measures for the mixed ataxia-spasticity phenotype, and patient stratification by genotype. Funding for natural history studies and biomarker development in spastic ataxia 4 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.
Archives of Neurology · 1997 · 31 citations
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.
Physical Therapy · 2007 · 30 citations · open access
Presentation and Progression of Friedreich Ataxia and Implications for Physical Therapist Examination
AbstractFriedreich ataxia, although rare, is the most prevalent inherited ataxia. Recent insight into the disease pathogenesis is creating new hope for effective therapies. The purposes of this update are: (1) to review the etiology, presentation, and progression of Friedreich ataxia and (2) to describe a comprehensive physical therapist examination emphasizing valid and reliable performance measurements associated with disease progression. Early identification of individuals with Friedreich ataxia and precise characterization of impairments and functional limitations gain importance as new drug therapies are considered.
International Journal of Molecular Sciences · 2020 · 6 citations · open access
Analyzing Gene Expression Profiles from Ataxia and Spasticity Phenotypes to Reveal Spastic Ataxia Related Pathways
AbstractSpastic ataxia (SA) is a group of rare neurodegenerative diseases, characterized by mixed features of generalized ataxia and spasticity. The pathogenetic mechanisms that drive the development of the majority of these diseases remain unclear, although a number of studies have highlighted the involvement of mitochondrial and lipid metabolism, as well as calcium signaling. Our group has previously published the GBA2 c.1780G > C (p.Asp594His) missense variant as the cause of spastic ataxia in a Cypriot consanguineous family, and more recently the biochemical characterization of this variant in patients’ lymphoblastoid cell lines. GBA2 is a crucial enzyme of sphingolipid metabolism. However, it is unknown if GBA2 has additional functions and therefore additional pathways may be involved in the disease development. The current study introduces bioinformatics approaches to better understand the pathogenetic mechanisms of the disease. We analyzed publicly available human gene expression datasets of diseases presented with ‘ataxia’ or ‘spasticity’ in their clinical phenotype and we performed pathway analysis in order to: (a) search for candidate perturbed pathways of SA; and (b) evaluate the role of sphingolipid signaling pathway and sphingolipid metabolism in the disease development, through the identification of differentially expressed genes in patients compared to controls. Our results demonstrate consistent differential expression of genes that participate in the sphingolipid pathways and highlight alterations in the pathway level that might be associated with the disease phenotype. Through enrichment analysis, we discuss additional pathways that are connected to sphingolipid pathways, such as PI3K-Akt signaling, MAPK signaling, calcium signaling, and lipid and carbohydrate metabolism as the most enriched for ataxia and spasticity phenotypes.
Journal of Drug Delivery and Therapeutics · 2014 · 1 citations · open access
A REVIEW ON FRIEDREICH ATAXIA, A NEURODEGENERATIVE DISORDER
AbstractThe present report discusses about the clinical trial requirements for Friedreich ataxia disease such as inclusion and exclusion criteria for the patients,primary/secondary outcome measuresrequired for assessing the efficacy of therapies viarating scales, physical activity tests, biomarkersand number of subjects/patients to be enrolled in each phase of the clinical trials of Friedreich ataxia (F.A.). These parameters have been selected from the ongoing and completed clinical trials for F.A. as reported in Clinical trials.gov and Friedreich Ataxia Research Alliance (FARA) official website. A total of 33 clinical trialdetails werereviewed for compilation of the above mentioned parameters. For the purpose of this report, the most useful and most commonly assessedprimary/secondary outcome measureswith respect to efficacy as well as inclusion and exclusion criteria have been selected and are being cited in this review.The outcome measures for the purpose of efficacy trials can broadly be classified as primary and secondaryoutcome measures and in each category, subclasses are being presented in the order of their priority as determined by their usefulness and common occurrence in all trials mentioned. These outcome measuresincludeRating Scales for Friedreich Ataxia, Physical Activity Tests and Biomarkers, evaluation of Cardiac functionality viz. left ventricular wall mass, non-invasive measures of systolic and diastolic ventricular function, echocardiography and immunogenicity.The genetic predisposition of Friedreich ataxia (epigenetics) leading to the pathogenesis of the disease is also discussed in this report. Based on above primary and secondary outcomes measures and inclusion and exclusion criteria, a tabular representation of the ongoing/ completed clinical trials representing the efficacy studies of the test molecules and the patient involvements in each clinical trial is also been listed. Various aspects of clinical trialsneeded for assessing ataxic stage in Friedreich ataxia disease is been reviewed in this article. Key words:Friedreich ataxia, Friedreich Ataxia Research Alliance (FARA), Inclusion and Exclusion criteria, primary and secondary outcome measures, rating scales, biomarkers, physical activity tests.
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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