DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Lafora disease — 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 moduleLafora disease 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 lafora disease 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
EPM2A glucan phosphatase, laforin (EPM2A) — EPM2A 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 4RKK · 2.4 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Lafora disease is a fatal autosomal recessive progressive myoclonus epilepsy. Patients develop myoclonus, tonic-clonic seizures, visual hallucinations, and cognitive decline beginning in adolescence, and typically die within ten years of onset. The disease is driven by abnormal carbohydrate deposits called Lafora bodies in the brain. Two genes are known to be involved: EPM2A, which encodes the dual-specificity phosphatase laforin, and NHLRC1 (EPM2B), which encodes the E3-ubiquitin ligase malin. Laforin is unique in humans as the only protein that can release phosphate from carbohydrates. The laforin-malin complex is thought to regulate glycogen synthesis, and is also involved in response to endoplasmic reticulum stress and misfolded protein clearance. However, controversial data and missing links still make it difficult to assess the concrete relationship between glycogen deregulation and neuronal damage.
Approximately 50% of Lafora disease cases are caused by mutations in EPM2A. Over 50 different laforin mutations have been described in patients. Not all mutations are the same; many may have milder effects on protein function. An unusual late-onset case was described in a patient who lived to age 59, carrying a novel mutation changing phenylalanine to cysteine at position 321 (F321C). Biochemical analysis of recombinant laforin F321C, along with a previously described F321S mutation, showed that these mutations only mildly alter laforin function, providing a biochemical explanation for the very mild clinical phenotype.
Despite these molecular insights, clinical treatments are far from being achieved. The review literature notes that one hundred years after the first description of Lafora bodies, the molecular bases of the disease are finally being elucidated, but no effective therapy exists. The biochemical analysis of patient mutations may enable personalised diagnosis and prediction of disease progression, but this remains at the level of laboratory characterisation.
What is still missing is a therapy that can prevent or reverse the accumulation of Lafora bodies in the brain, or halt the neurodegeneration that follows. No clinical trial data for any drug are reported in these abstracts. The field lacks a treatment that has been tested in patients, and the heterogeneity of laforin mutations means that any future therapy may need to account for individual patient genetics. Funding for translational work, a viable trial design, and patient stratification by mutation severity are all 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.
FEBS Journal · 2012 · 74 citations · open access
Laforin, a protein with many faces: glucan phosphatase, adapter protein, et alii
AbstractLafora disease (LD) is a rare, fatal neurodegenerative disorder characterized by the accumulation of glycogen-like inclusions in the cytoplasm of cells from most tissues of affected patients. One hundred years after the first description of these inclusions, the molecular bases underlying the processes involved in LD physiopathology are finally being elucidated. The main cause of the disease is related to the activity of two proteins, the dual-specificity phosphatase laforin and the E3-ubiquitin ligase malin, which form a functional complex. Laforin is unique in humans, as it is composed of a carbohydrate-binding module attached to a cysteine-based catalytic dual-specificity phosphatase domain. Laforin directly dephosphorylates glycogen, but other proteinaceous substrates, if they exist, have remained elusive. Recently, an emerging set of laforin-binding partners apart from malin have been described, suggestive of laforin roles unrelated to its catalytic activity. Further investigations based on different transgenic mouse models have shown that the laforin-malin complex is also involved in other cellular processes, such as response to endoplasmic reticulum stress and misfolded protein clearance by the lysosomal pathway. However, controversial data and some missing links still make it difficult to assess the concrete relationship between glycogen deregulation and neuronal damage leading to the fatal symptoms observed in LD patients, such as myoclonic seizures and epilepsy. Consequently, clinical treatments are far from being achieved. In the present review, we focus on the knowledge of laforin biology, not only as a glucan phosphatase, but also as an adaptor protein involved in several physiological pathways.
Recent Patents on Endocrine Metabolic & Immune Drug Discovery · 2012 · 6 citations · open access
Lafora Progressive Myoclonus Epilepsy: Recent Insights into Cell Degeneration
AbstractLafora disease (LD) is a fatal autosomal recessive form of progressive myoclonus epilepsy. Patients manifest myoclonus and tonic-clonic seizures, visual hallucinations, intellectual, and progressive neurologic deterioration beginning in adolescence. The two genes known to be involved in Lafora disease are EPM2A and NHLRC1 (EPM2B). The EPM2A gene encodes laforin, a dual-specificity protein phosphatase, and the NHLRC1 gene encodes malin, an E3- ubiquitin ligase. The two proteins interact with each other and, as a complex, are thought to regulate glycogen synthesis. It may also be considered as a disorder of carbohydrate metabolism because of the formation of polyglucosan inclusion bodies in neural and other tissues due to abnormalities of the proteins laforin or malin. The review also outlines important patents related to Lafora disease. Keywords: Brain, brain diseases, central nervous system, lafora disease, laforin, malin, neurodegenerative diseases, autosomal recessive, Lafora disease, glycogen synthase activity
Personalized Diagnosis for Lafora Disease, a Fatal Epilepsy
AbstractLafora disease (LD) is a fatal, genetic disorder characterized by progressive neurodegeneration, myoclonus (i.e. uncontrolled muscle spasms), and epilepsy. LD patients present with seizures in adolescence that become increasingly severe and frequent, suffer rapid cognitive decline, and typically die within ten years of onset. Abnormal carbohydrate deposits known as Lafora bodies are found in the brains of LD patients and have been shown to drive disease progression. Approximately 50% of LD cases are caused by mutations in the Epilepsy progressive myoclonus 2A ( EPM2A ) gene that encodes a protein called laforin. Laforin is the only protein in humans that can release phosphate from carbohydrates. In LD patients, mutations in laforin lead to excess phosphate and abnormal branching in cellular carbohydrate stores, causing carbohydrate accumulation and toxicity. There are >50 different laforin mutations that have been described in LD patients, and some patients have milder forms of the disease. We have shown that not all laforin mutations are the same and that many mutations may have milder effects on protein function. Our biochemical analysis of disease mutations would allow us to predict disease outcome based on a patient's individual genetics. Recently an unusual case of late‐onset LD was described in a patient who lived to the age of 59. This patient contained a novel laforin mutation, where a specific amino acid at position 321 was changed from a phenylalanine to a cysteine (F321C). The objective of this study was to determine the effect of the F321C mutation on laforin function. We generated and purified recombinant laforin F321C, tested its biochemical effects using activity, binding, and stability assays, and found that this mutation and a previously described LD patient mutation, F321S, only mildly alter the function of laforin, providing a biochemical explanation for the very mild clinical phenotype. Our studies also establish a biochemical avenue for rapid, personalized diagnoses of LD patients, enabling doctors to predict patient progression and design treatment schemes that are specific to patients. Support or Funding Information This study was supported by NIH Grants F31NS093892 (M.K.B), R01NS070899 and P01NS097197 (M.S.G.), and NSF Grant IIA‐1355438 (M.S.G.). This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
Russian Journal of Archive of Pathology · 2022 · 0 citations
Lafora disease with a fatal outcome
Abstract<h3></h3> Болезнь Лафоры представляет собой редкую наследственную патологию нервной системы (группа прогрессирующих миоклонических эпилепсий), особым морфологическим признаком которой является наличие в тканях головного мозга, сердечной мышцы, печени, эпителии протоков потовых желез специфических аномальных структур — полиглюкозановых телец (тельца Лафоры). В статье рассмотрены клинические данные течения болезни Лафоры у 18-летней пациентки с летальным исходом и результаты патолого-анатомического исследования. Диагноз заболевания подтвержден данными генетического анализа — наличием гомозиготной мутации во 2-м экзоне гена <i>EPM2A</i> — лафорина (chr6:146007412G>A, rs137852915). При анализе источников литературы мы не нашли описания наблюдений болезни Лафоры с летальным исходом с представлением данных макроскопического исследования при аутопсии, а также результатов патогистологической оценки измененных тканей внутренних органов с наличием специфических для указанной патологии морфологических проявлений (тельца Лафоры в веществе головного мозга, сердце, эпителии потовых желез).
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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