DeCure for Autosomal recessive ataxia, Beauce type
DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for autosomal recessive ataxia, Beauce type — screening already-approved drugs against its 2-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, Beauce type maps to a 2-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, beauce type 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
spectrin repeat containing nuclear envelope protein 1 (SYNE1) — SYNE1 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 pgedrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6R15 · 1.82 Å · ligand TRIETHYLENE GLYCOL (PGE). Experimental structure, not a prediction.
What the evidence adds up to
The 1998 study of 361 ataxia families found that among 178 dominant kindreds, trinucleotide repeat expansions accounted for 61% of cases, with SCA3 the most common at 20.8%. Among apparently recessive patients, 11.4% carried Friedreich ataxia (FA) alleles, but these had relatively small repeat sizes (90–600 GAA repeats on the smaller allele) and atypical clinical features such as adult onset, retained tendon reflexes, and normal plantar responses. The authors concluded that patients without a clear dominant pattern should be screened for expansions at both FA and dominant ataxia loci.
By 2009, autosomal recessive ataxias had grown to encompass more than 20 clinical entities and an even larger number of associated genes. Some disorders were noted to be very rare and restricted to isolated populations, while others were found worldwide. An expressive number of recessive ataxias were described as treatable, placing a high responsibility on accurate diagnosis. A 2020 retrospective analysis of 31 Turkish children with autosomal recessive cerebellar ataxia found a mean age at symptom onset of 46 months, and 67.7% came from consanguineous marriages. The most common diagnoses were Friedreich ataxia (8 patients), ataxia telangiectasia (5), L-2-hydroxyglutaric aciduria (3), and Joubert syndrome (3); the remaining 12 patients had one of eight other rare recessive disorders.
A 2022 systematic review of therapeutic interventions in Friedreich ataxia identified 32 eligible publications, 24 of which were randomised controlled trials. The most frequently studied drug was idebenone (11 trials), followed by recombinant erythropoietin (6), omaveloxolone (3), and amantadine hydrochloride (2). Patients ranged from 8 to 73 years old, with disease duration from 4.7 to 19 years. 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 deterioration at 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. Other treatments did not show evidence of significant improvement. Serious adverse events were rare: one atrial fibrillation, one craniocerebral injury, and one ventricular tachycardia.
What is still missing is a clear understanding of which patient subgroups might benefit from which drug, given the genetic and clinical heterogeneity of recessive ataxias. Most trials were short, making it difficult to detect effects on slow disease progression. No drug has been approved for Friedreich ataxia, and the systematic review concluded that novel efficacious drugs are needed. For the rarer recessive ataxias, even basic natural history data and validated outcome measures are lacking, and funding for trials in these small, often isolated populations remains scarce.
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 · 1998 · 238 citations
Incidence of dominant spinocerebellar and Friedreich triplet repeats among 361 ataxia families
AbstractOBJECTIVE: To determine the incidence of spinocerebellar ataxia (SCA) types 1, 2, 3, 6, and 7 and Friedreich's ataxia (FA) among a large panel of ataxia families. BACKGROUND: The ataxias are a clinically and genetically heterogeneous group of neurodegenerative diseases that variably affect the cerebellum, brainstem, and spinocerebellar tracts. Trinucleotide repeat expansions have been shown to be the mutational mechanism for five dominantly inherited SCAs as well as FA. METHODS: We collected DNA samples and clinical data from patients representing 361 families with adult-onset ataxia of unknown etiology. Patients with a clinical diagnosis of FA were specifically excluded from our collection. RESULTS: Among the 178 dominant kindreds, we found SCA1 expansion at a frequency of 5.6%, SCA2 expansion at a frequency of 15.2%, SCA3 expansion at a frequency of 20.8%, SCA6 expansion at a frequency of 15.2%, and SCA7 expansion at a frequency of 4.5%. FA alleles were found in 11.4% of apparently recessive and 5.2% of apparently sporadic patients. Among these patients the repeat sizes for one or both FA alleles were relatively small, with sizes for the smaller allele ranging from 90 to 600 GAA repeats. The clinical presentation for these patients is atypical for FA, with one or more of the following characteristics: adult onset of disease, retained tendon reflexes, normal plantar response, and intact or partially intact sensory perceptions. CONCLUSIONS: Pathogenic trinucleotide repeat expansions were found among 61% of the dominant kindreds. Among patients with apparently recessive or negative family histories of ataxia, 6.8% and 4.4% tested positive for a CAG expansion at one of the dominant loci, and 11.4 and 5.2% of patients with apparently recessive or sporadic forms of ataxia had FA expansions. Because of the significant implications that a dominant versus recessive inheritance pattern has for future generations, it is important to screen patients who do not have a clearly dominant inheritance pattern for expansions at both the FA and the dominant ataxia loci.
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.
Arquivos de Neuro-Psiquiatria · 2009 · 44 citations · open access
Autosomal recessive ataxias: 20 types, and counting
AbstractMore than 140 years after the first description of Friedreich ataxia, autosomal recessive ataxias have become one of the more complex fields in neurogenetics. Currently this group of diseases contains more than 20 clinical entities and an even larger number of associated genes. Some disorders are very rare, restricted to isolated populations, and others are found worldwide. An expressive number of recessive ataxias are treatable, and responsibility for an accurate diagnosis is high. The purpose of this review is to update the practitioner on clinical and pathophysiological aspects of these disorders and to present an algorithm to guide the diagnosis.
Journal of Pediatric Neurosciences · 2020 · 6 citations · open access
Clinical features and molecular genetics of autosomal recessive ataxia in the Turkish population
Abstract<b>Background:</b> Autosomal recessive cerebellar ataxias (ARCAs) are a heterogeneous group of inherited neurodegenerative disorders. The aim of this study was to present the clinical and genetic features of patients with ataxia complaints and those genetically diagnosed with ARCAs. <b>Materials and Methods:</b> Thirty-one children with ARCA were retrospectively analyzed. <b>Results:</b> Fourteen (45.2%) were boys and 17 (54.8%) were girls with the mean age at onset of symptoms of 46.13 ± 26.30 months (12–120 months). Of the 31 patients, 21 (67.7%) were from consanguineous marriages. Eight patients had Friedreich’s ataxia, five had ataxia telangiectasia, three had <sc>l</sc>-2-hydroxyglutaric aciduria, three had Joubert syndrome, two had neuronal ceroid lipofuscinosis, two had megalencephalic leukoencephalopathy with subcortical cysts, two had ataxia with ocular motor oculomotor apraxia type 1, one had cytochrome <i>c</i> oxidase deficiency, one had autosomal recessive spastic ataxia of Charlevoix-Saguenay, one had Niemann-Pick type C, one had congenital disorders of glycosylation, one had adrenoleukodystrophy, and one had cobalamin transport disorder. <b>Conclusion:</b> The prevalence of hereditary ataxia can vary among countries. The consanguineous marriage is an important finding in these diseases. These genetic tests will increase the number of ARCA patients diagnosed.
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.
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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