DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Leigh syndrome — screening already-approved drugs against its 29-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleLeigh syndrome maps to a 29-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 leigh syndrome 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
dihydrolipoamide dehydrogenase (DLD) — DLD 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 faddrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6I4R · 1.439 Å · ligand FLAVIN-ADENINE DINUCLEOTIDE (FAD). Experimental structure, not a prediction.
What the evidence adds up to
Leigh syndrome is a rare, progressive neurodegenerative condition caused by pathogenic genetic variants in mitochondrial or nuclear DNA. Its natural history is not well understood and has not been rigorously studied. An observational prospective cohort study, the Leigh Syndrome Roadmap Project, is currently evaluating the natural history of the disease by administering outcome measures in disease-relevant domains to patients at 3-6 month intervals, and also evaluating retrospective medical history-based objective outcomes. The goal is to improve understanding of the disease course and to develop robust outcome measures for use in future clinical trials.
Diagnosing Leigh syndrome requires the presence of typical lesions on cerebral MRI, usually symmetric T2 hyperintensities in the brainstem, cerebellum, basal ganglia, or thalamus. A 2023 letter to the editor disputed a reported diagnosis of Leigh syndrome in a 1-year-old female with a homozygous NDUFS8 variant because her cerebral MRI at 5 months was normal. That patient presented with irritability, continuous crying, seizures, nystagmus, ataxia, dysphagia, muscle weakness, and vomiting, was treated with coenzyme-Q, thiamine, and diazepam, and died at age 1 from cardio-respiratory arrest following aspiration. The letter noted that the study did not report EEG results, did not clarify the course of epilepsy or the meaning of the term "weak seizure," and did not discuss whether muscle weakness was due to encephalopathy or peripheral nervous system involvement, nor whether creatine kinase was elevated.
A 2020 analysis of a 20-year cohort aimed to provide a detailed description of central nervous system lesions in Leigh syndrome and their biological evolution in view of genetic and clinical findings, adding insights including association with overlapping syndromes and correlation of pathogenic genetic variants with neuroimaging phenotypes. A 2021 review states that Leigh syndrome is incurable, with a poor prognosis and no current substantial treatment options, though multiple studies are underway to understand its etiology, pathogenesis, and pathophysiology.
What is still missing are completed natural history studies with sufficient patient numbers to define robust, clinically meaningful endpoints; validated outcome measures that can be used in future trials; and any therapy that has demonstrated efficacy in a controlled trial. The field also lacks clear consensus on diagnostic criteria that account for the expanding genetic aetiologies, and adequate patient stratification by genotype and phenotype for trial design.
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 · 2003 · 42 citations
Remarkable improvement in adult Leigh syndrome with partial cytochrome <i>c</i> oxidase deficiency
AbstractLeigh syndrome (LS) is a heterogeneous disorder, usually due to a defect in oxidative metabolism. Typically, signs and symptoms commence in infancy or childhood, although rare cases of adult onset have been described. Progressive deterioration is the norm. The authors describe a 22-year-old woman with partial cytochrome c oxidase deficiency who developed fulminant LS following an acute febrile illness and who subsequently showed dramatic clinical and neuroradiologic improvement.
Murdoch Childrens Research Institute (MCRI) · 2024 · 0 citations · open access
Leigh Syndrome Roadmap Project (LSRP): A Natural History Study
AbstractLeigh Syndrome (LS) is a rare, progressive neurodegenerative condition caused by pathogenic genetic variants in mitochondrial or nuclear DNA. The natural history of LS is not well understood and has not been rigorously studied. To improve outcomes for patients and develop robust clinical trials for the treatment of this disease, it is important to study the natural history of the disease and evaluate outcome measures for use in future clinical trials. Therefore, this is an observational prospective cohort study evaluating the natural history of LS. Outcome measures in disease-relevant domains will be administered to patients with LS at 3-6 month intervals. Retrospective medical history-based objective outcomes will also be evaluated.
Murdoch Childrens Research Institute (MCRI) · 2024 · 0 citations · open access
Leigh Syndrome Roadmap Project (LSRP): A Natural History Study
AbstractLeigh Syndrome (LS) is a rare, progressive neurodegenerative condition caused by pathogenic genetic variants in mitochondrial or nuclear DNA. The natural history of LS is not well understood and has not been rigorously studied. To improve outcomes for patients and develop robust clinical trials for the treatment of this disease, it is important to study the natural history of the disease and evaluate outcome measures for use in future clinical trials. Therefore, this is an observational prospective cohort study evaluating the natural history of LS. Outcome measures in disease-relevant domains will be administered to patients with LS at 3-6 month intervals. Retrospective medical history-based objective outcomes will also be evaluated.
Frío-calor y aire acondicionado · 2004 · 0 citations
El control de la temperatura por zonas: sistemas con control de temperatura independiente. Análisis comparativo, ventajas e inconvenientes de los sistemas de climatización aplicables
AbstractThe neurodiagnostic criteria of Leigh syndrome have not yet been clearly redefined based on the expanding of molecular etiologies. We aimed to analyze 20 years of clinical, genetic, and magnetic resonance studies from our Leigh syndrome cohort to provide a detailed description of central nervous system lesions in Leigh syndrome and their biological evolution in view of their genetic and clinical findings. Our study adds new neurodiagnostic insights to the current knowledge of Leigh syndrome, including association with overlapping syndromes, and the correlation of pathogenic genetic variants with neuroimaging phenotypes. ANN NEUROL 2020;88:218-232.
Clinical Case Reports · 2023 · 0 citations · open access
Diagnosing Leigh syndrome requires typical lesions on cerebral MRI
AbstractLetter to the Editor We read with interest the article by Shabannejadian et al. on a 1-year-old female with Leigh syndrome due to the homozygous, missense variant c.484G>A in exon 6 of the NDUFS8 gene.1 The variant manifested phenotypically with irritability, continuous crying, seizures, nystagmus, ataxia, dysphagia, muscle weakness, and vomiting.1 Despite normal cerebral magnetic resonance imaging (MRI), the patient was diagnosed with Leigh syndrome and coenzyme-Q, thiamine, and diazepam were prescribed.1 The patient died at age 1 from cardio-respiratory arrest following aspiration.1 The study is compelling but has limitations that should be discussed. We disagree with the diagnosis of Leigh syndrome in the index patient. Diagnosing Leigh syndrome requires the presence of typical lesions on cerebral MRI. These are usually symmetric T2 hyperintensities in the brainstem, cerebellum, basal ganglia, or thalamus.2 Since the index patient had a normal cerebral MRI at age 5 months, the diagnosis of Leigh syndrome should be revised. There is no mention on the development of epilepsy. We should know whether the patient suffered only a single seizure at age 5 months or whether seizures recurred. We also should know whether only diazepam was given as long-term treatment of epilepsy or whether other antiseizure drugs (ASDs) were added. A limitation in this respect is that results of electroencephalography (EEG) recording were not reported. Knowing the course of epilepsy is crucial as it can strongly determine the outcome of patients with a mitochondrial disorder (MID). We should also know what the authors mean with the term “weak seizure”.1 Do the authors mean a focal seizure, a short-lasting seizure, or seizures with preserved consciousness and only mild convulsions? Regarding the pedigree shown in figure 3, it is surprising that the grand-grandmother of the index patient was indicated as a carrier of the NDUFS8 variant. Was she alive and did she really undergo genetic testing? Furthermore, we should know whether any of the nine heterozygous carriers of the culprit NDUFS8 variant manifested phenotypically. A limitation of the study is that it is not discussed whether muscle weakness was due to encephalopathy or due to affection of the peripheral nervous system (PNS). Regarding a suspected PNS lesion, it would be interesting to know whether the patient had myopathy and whether creatine kinase (CK) was elevated. Overall, the interesting study has limitations that put the results and their interpretation into perspective. Addressing these issues would strengthen the conclusions and could improve the status of the study. Diagnosing Leigh syndrome requires typical lesions on cerebral MRI. Josef Finsterer: Investigation; methodology; validation. None. Financial disclosures for the previous 12 months: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Written informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy. All data are available from the corresponding author. The authors confirm that the approval of an institutional review board or patient consent was not required for this work. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
INDIGO (University of Illinois at Chicago) · 2021 · 0 citations · open access
Table_2_Leigh Syndrome: A Tale of Two Genomes.docx
Abstract<p>Leigh syndrome is a rare, complex, and incurable early onset (typically infant or early childhood) mitochondrial disorder with both phenotypic and genetic heterogeneity. The heterogeneous nature of this disorder, based in part on the complexity of mitochondrial genetics, and the significant interactions between the nuclear and mitochondrial genomes has made it particularly challenging to research and develop therapies. This review article discusses some of the advances that have been made in the field to date. While the prognosis is poor with no current substantial treatment options, multiple studies are underway to understand the etiology, pathogenesis, and pathophysiology of Leigh syndrome. With advances in available research tools leading to a better understanding of the mitochondria in health and disease, there is hope for novel treatment options in the future.</p>
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.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
