DeCure for Autosomal recessive ataxia due to ubiquinone deficiency
DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for autosomal recessive ataxia due to ubiquinone deficiency — 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 moduleAutosomal recessive ataxia due to ubiquinone deficiency 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 autosomal recessive ataxia due to ubiquinone deficiency 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
Fourteen patients with autosomal recessive cerebellar ataxia 2 (ARCA2) due to ADCK3 mutations and ubiquinone deficiency were studied. First signs appeared before adulthood in all. Cerebellar atrophy was present in every case. The ataxia was very slowly progressive or apparently stable, not the inexorable course typical of other childhood-onset recessive ataxias. Two patients suffered stroke-like episodes that caused significant neurological deterioration. Two patients treated with ubidecarenone showed marked improvement in movement disorders including ataxia. No correlation was found between genotype and phenotype. The authors suggest that patients with a slowly progressive ataxia plus other central nervous system signs, or with cerebellar atrophy and a stroke-like episode, should undergo ADCK3 molecular analysis.
A systematic review of interventions in Friedreich ataxia identified 32 publications, 24 of them randomised controlled trials. The most studied drug was idebenone (11 trials), followed by recombinant erythropoietin (6), omaveloxolone (3), and amantadine hydrochloride (2). Single trials existed for A0001, CoQ10, creatine, deferiprone, interferon-γ-1b, L-carnitine, 5-hydroxytryptophan, luvadaxistat, resveratrol, RT001, and vatiquinone. In many studies, patients deteriorated on severity scales regardless of treatment, or results were inconclusive. Idebenone at 1350–2550 mg per day showed improvement in ICARS and FARS scores at 6 months, but scores deteriorated after 12 months in ambulatory patients. Omaveloxolone at 2.5–300 mg per day showed significant improvement in mFARS and activities of daily living scores at 48 weeks versus placebo. Vatiquinone showed significant improvement in FARS-neuro scores at 24 months versus natural disease progression. Serious adverse events across all trials were atrial fibrillation (one case), craniocerebral injury (one), and ventricular tachycardia (one). The review concluded that there is a considerable unmet need for interventions that halt or slow the deteriorating nature of Friedreich ataxia.
A separate epidemiological study of Friedreich ataxia in northwestern Italy identified 59 cases diagnosed between 1945 and 1984. Point prevalence was 1.2 per 100,000. Birth incidence was 1 per 36,000 live births. The ratio of first-cousin marriages among parents was 3%, lower than the 8% expected under Dahlberg's formula, which the authors state is not compatible with genetic heterogeneity for Friedreich ataxia.
A polyherbal formulation called SAAAB was evaluated for ataxia associated with hypertension and diabetes, with a reported decrease in ICARS score after six months of supplementation. The abstract does not provide patient numbers, baseline scores, or a control group. UBA5 mutations were identified in two Chinese siblings with autosomal recessive cerebellar ataxia, but no treatment data are given.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Orphanet Journal of Rare Diseases · 2013 · 74 citations · open access
Phenotypic variability in ARCA2 and identification of a core ataxic phenotype with slow progression
AbstractAutosomal recessive cerebellar ataxia 2 (ARCA2) is a recently identified recessive ataxia due to ubiquinone deficiency and biallelic mutations in the ADCK3 gene. The phenotype of the twenty-one patients reported worldwide varies greatly. Thus, it is difficult to decide which ataxic patients are good candidates for ADCK3 screening without evidence of ubiquinone deficiency. We report here the clinical and molecular data of 10 newly diagnosed patients from seven families and update the disease history of four additional patients reported in previous articles to delineate the clinical spectrum of ARCA2 phenotype and to provide a guide to the molecular diagnosis. First signs occurred before adulthood in all 14 patients. Cerebellar atrophy appeared in all instances. The progressivity and severity of ataxia varied greatly, but no patients had the typical inexorable ataxic course that characterizes other childhood-onset recessive ataxias. The ataxia was frequently associated with other neurological signs. Importantly, stroke-like episodes contributed to significant deterioration of the neurological status in two patients. Ubidecarenone therapy markedly improved the movement disorders, including ataxia, in two other patients. The 7 novel ADCK3 mutations found in the 10 new patients were two missense and five truncating mutations. There was no apparent correlation between the genotype and the phenotype. Our series reveals that the clinical spectrum of ARCA2 encompasses a range of ataxic phenotypes. On one end, it may manifest as a pure ataxia with very slow progressivity and, on the other end, as a severe infantile encephalopathy with cerebellar atrophy. The phenotype of most patients, however, lies in between. It is characterized by a very slowly progressive or apparently stable ataxia associated with other signs of central nervous system involvement. We suggest undergoing the molecular analysis of ADCK3 in patients with this phenotype and in those with cerebellar atrophy and a stroke-like episode. The diagnosis of patients with a severe ARCA2 phenotype may also be performed on the basis of biological data, i.e. low ubiquinone level or functional evidence of ubiquinone deficiency. This diagnosis is crucial since the neurological status of some patients may be improved by ubiquinone therapy.
Friedreich's ataxia: a descriptive epidemiological study in an Italian population
AbstractAll the cases of Friedreich's ataxia (FA) diagnosed between 1945 through 1984 among residents of a defined area of northwestern Italy were ascertained (N = 59). Cases were diagnosed according to the criteria of the "Quebec Cooperative Study on Friedreich's Ataxia (QCSFA)" with minor modifications. We identified 39 families with 47 probands and 12 secondary cases. Therefore ascertainment probability was 80%. Male to female ratio was 1:1. Pedigrees were compatible with autosomal recessive inheritance. Segregation ratio was 0.28 with both Weinberg's method and the "singles" method (under incomplete ascertainment). Point prevalence ratio was 1.2/100,000 population. Birth incidence rate was 1/36,000 live births. Gene frequency was estimated to be 1/191. The ratio of first-cousin marriages observed among parents of FA patients (3%) was lower than expected from Dahlberg's formula (8%). This finding is not compatible with the hypothesis of genetic heterogeneity for FA.
IOSR Journal of Pharmacy and Biological Sciences · 2014 · 1 citations · open access
Evaluation of SAAAB as a Polyherbal Formulation for the Treatment of Ataxia
AbstractAtaxia is a complication of high blood pressure and diabetes with a clear cut deficiency of ubiquinone central to depletion of vitamins notably vitamin E. this study therefore sought to determine the presence of ubiquinone contained in SAAAB as it was evidence in a remarkable improvement in area of cerebral dysfunction improvement and a notable decrease in the ICARS' score after six months of supplementation.
Sage Journals Data · 2022 · 0 citations · open access
Clinical evidence of interventions assessed in Friedreich ataxia: a systematic review
AbstractObjectives:The rare inherited autosomal recessive disease Friedreich ataxia (FA) causes progressive neurodegenerative changes and disability in patients. A systematic literature review (SLR) was carried out to understand and summarize the published efficacy and safety of therapeutic interventions in this disease.Methods:Database searches were carried out in MEDLINE, Embase, and Cochrane by two independent reviewers. In addition, trial registries and conference proceedings were hand-searched.Results:Thirty-two publications were deemed eligible according to PICOS criteria. Twenty-four publications detail randomized controlled trials. The most frequently identified therapeutic intervention was idebenone (<i>n</i> = 11), followed by recombinant erythropoietin (<i>n</i> = 6), omaveloxolone (<i>n</i> = 3), and amantadine hydrochloride (<i>n</i> = 2). Other therapeutic interventions were investigated in one publication: A0001, CoQ10, creatine, deferiprone, interferon-γ-1b, the L-carnitine levorotatory form of 5-hydroxytryptophan, luvadaxistat, resveratrol, RT001, and vatiquinone (EPI-743). These studies included patients from 8 to 73 years old, and disease duration varied from 4.7 to 19 years. Disease severity as per the mean GAA1 and GAA2 allele repeat length ranged from 350 to 930 and 620 to 987 nucleotides, respectively. Most frequently reported efficacy outcomes were the International Cooperative Ataxia Rating Scale (ICARS, <i>n</i> = 10), the Friedreich Ataxia Rating Scale (modified FARS and FARS-neuro, <i>n</i> = 12), the Scale for Assessment and Rating of Ataxia (SARA, <i>n</i> = 7), and the Activities of Daily Living scale (ADL, <i>n</i> = 8). Each of these assesses the severity of disability in FA patients. In many studies, patients with FA deteriorated according to these severity scales regardless of treatment, or inconclusive results were found. Generally, these therapeutic interventions were well-tolerated and safe. Serious adverse events were atrial fibrillation (<i>n</i> = 1), craniocerebral injury (<i>n</i> = 1), and ventricular tachycardia (<i>n</i> = 1).Conclusion:Identified literature showed a considerable unmet need for therapeutic interventions that halt or slow the deteriorating nature of FA. Novel efficacious drugs should be investigated that aim to improve symptoms or slow disease progression.Plain Language Summary<b>A systematic review investigating the effectiveness and safety of treatments for Friedreich ataxia</b><b>What is Friedreich ataxia?</b>Friedreich ataxia (FA) is a rare genetic condition that causes nervous system damage and movement problems, including muscle weakness and impaired coordination (ataxia). Heart problems, vision problems, spine problems, and diabetes can occur, too. Within 10 to 20 years of the first symptoms, an individual with FA generally requires a wheelchair.<b>Why was this study done?</b>Currently there are no approved treatments for FA. Current treatments focus on relieving symptoms. This study was carried out to obtain a landscape view of all the published evidence about FA treatments.<b>What did the researchers find?</b>• Two scales were most frequently used to assess disease severity: the International Cooperative Ataxia Rating Scale (ICARS) and the FA Rating Scale (modified FARS and FARS-neuro).• Patients on idebenone at 1350 to 2550 mg per day showed improvement in ICARS and FARS scores over 6 months, but scores deteriorated after 12 months in ambulatory patients with FA.• Omaveloxolone at doses of 2.5 to 300 mg per day showed significant improvement in mFARS scores and FA Activity of Daily Living scores at 48 weeks compared with placebo.• Patients treated with vatiquinone showed significant improvements in FARS-neuro scores at 24 months <i>versus</i> natural disease progression.• Other treatments did not show evidence of significant improvement.<b>What does this mean?</b>FA leads to nervous system damage slowly, over an extended period. It is important to keep in mind that many of the studies reviewed here were of fairly short duration, meaning that the effects of a treatment may not have been detectable.<b>Why is this important?</b>This study was undertaken in the hopes that a comprehensive picture of the current treatment landscape for FA will help promote research that will eventually lead to effective treatments to slow down or reverse the damage caused by disease, which are vitally needed.
UBA5 mutations cause a new form of autosomal recessive cerebellar ataxia
AbstractAutosomal recessive cerebellar ataxia (ARCA) comprises a large and heterogeneous group of neurodegenerative disorders. Through whole-exome sequencing, we identified compound heterozygous mutations in ubiquitin-like modifier activating enzyme 5 gene (<i>UBA5</i>) in two Chinese siblings presenting with ARCA.
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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