DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for myopathy — screening already-approved drugs against its 34-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleMyopathy maps to a 34-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 myopathy 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
acyl-CoA dehydrogenase very long chain (ACADVL) — ACADVL 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 7S7G · 1.34 Å · ligand FLAVIN-ADENINE DINUCLEOTIDE (FAD). Experimental structure, not a prediction.
What the evidence adds up to
A 2023 study of 80 patients with RYR1-related myopathy (40 dominant, 31 recessive, 6 de novo dominant, 3 uncertain) seen at two UK centres between 1992 and 2019 reported that 15% of patients older than two years never walked, and 7% lost ambulation during follow-up. Scoliosis occurred in 30%, spinal rigidity in 17%, respiratory involvement in 22%, and 12% required ventilatory support from a median age of seven years. Feeding difficulties affected 30%, and 57% of those needed gastrostomy or tube feeding. Recessive patients had more severe prenatal and neonatal features, but longitudinal analysis showed a less progressive course: annual change in forced vital capacity was -0.2%/year in recessive versus -1.4%/year in dominant patients. No anaesthetic-induced malignant hyperthermia episodes were reported.
Functional analysis of three RYR1 variants in a family with suspected myopathy and malignant hyperthermia susceptibility found that the p.Trp661* nonsense variant produced a non-functional calcium channel and should be considered a risk factor for myopathy. The p.Asn2342Ser variant produced a hypersensitive channel and, when expressed as a compound heterozygote with a nonsense mutation on the second allele, is likely to cause malignant hyperthermia susceptibility. The role of the p.Pro816Leu variant remained unclear.
A 2019 review of toxic myopathies states that muscle symptoms are common among statin users and usually reverse after stopping the drug, but statins can rarely trigger an immune-mediated necrotising myopathy that persists and requires immunomodulatory therapy. Autoantibodies targeting 3-hydroxy-3-methylglutaryl coenzyme A reductase can distinguish the toxic and immune-mediated forms. Immune checkpoint inhibitors used in advanced cancer have been associated with inflammatory myositis. Reversible mitochondrial myopathy has been linked to zidovudine, and risk has been reported with newer antivirals such as telbivudine and raltegravir. Other drugs commonly associated with myopathy include amiodarone, chloroquine, hydroxychloroquine, colchicine, and corticosteroids, and myopathy can occur with chronic alcoholism. Stopping the offending agent reverses symptoms in most cases, except when immune-mediated injury is triggered.
A 1995 case report describes a 12-year-old girl who developed severe autoimmune thrombocytopenia after bone marrow transplant for acute lymphoblastic leukaemia. Epsilon-aminocaproic acid helped control bleeding but caused a rare myopathy, which resolved when the drug was discontinued and a different antifibrinolytic agent was used. A 2011 review of inflammatory myopathies notes that the muscle microenvironment involves adaptive and innate immune cells, cytokines, chemokines, and non-immune mechanisms such as endoplasmic reticulum stress and autophagy, but the mechanisms of muscle degeneration are not clearly defined. A 2005 review of distal myopathies describes identification of genes and mutations for early-onset (Laing) myopathy, tibial (Udd) myopathy, and distal myopathy with rimmed vacuoles (Nonaka), which is allelic with quadriceps-sparing hereditary inclusion body myopathy, and notes new diagnostic approaches using MRI and a blood-based assay for dysferlin deficiency. What is still missing for most of these myopathies are adequately powered longitudinal natural history studies, validated biomarkers for disease progression and treatment response, and clinical trials that stratify patients by genetic subtype or underlying mechanism.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Current Opinion in Rheumatology · 2011 · 36 citations
An update on pathogenic mechanisms of inflammatory myopathies
AbstractPURPOSE OF REVIEW: Our understanding of the pathogenesis of the inflammatory myopathies suggests an interplay between adaptive, innate immune, and nonimmune mechanisms in the damage and dysfunction that occur in myopathic muscle tissue. This review gives an update on the recent findings concerning some of these mechanisms and their relevance to disease diagnosis, prognosis, and therapy. RECENT FINDINGS: The presence of several additional immune cell types (CD-28 null T cells, regulatory T cells, plasmacytoid dendritic cells, plasma cells) and their roles in the various subsets of myositis are discussed. Likewise several new autoantibodies (e.g. 3-hydroxy-3 methylglutaryl-coenzyme-A reductase and melanoma differentiation-associated gene 5) and their association with disease phenotype are described. The review also discusses emerging evidence that cytokines (type 1 interferon) and Toll-like receptor signaling influence the local immune cell activation and response. The mechanisms involved in muscle degeneration are not clearly defined, but recent studies point to a role for nonimmune mechanisms such as endoplasmic reticulum stress and autophagy in skeletal muscle cell death and dysfunction in myositis. SUMMARY: The muscle microenvironment in inflammatory myopathy is complex. Multiple players such as adaptive and innate immune cells, cytokines, and chemokines as well as nonimmune mechanisms are involved. Understanding the nature of the relevant cell types and the molecular pathways underlying particular disease phenotypes should help to define therapeutic targets for myositis.
Current Opinion in Neurology · 2005 · 27 citations
Distal myopathies
AbstractPURPOSE OF REVIEW: The distal myopathies are a heterogeneous group of disorders that pose a challenge to both the clinician and geneticist. This article summarizes the findings of recent clinical, genetic and molecular studies and the current diagnostic approach to this group of patients. RECENT FINDINGS: Publications over the past 5 years describe a number of new clinical phenotypes and genetic loci and further emphasize the overlap in clinical phenotype between a number of these disorders and between the distal and limb girdle myopathies and hereditary inclusion body myopathies. Recent studies have led to the identification of the genes and mutations responsible for early onset (Laing) myopathy and tibial (Udd) myopathy, and for distal myopathy with rimmed vacuoles (Nonaka), which has been shown to be allelic with quadriceps sparing hereditary inclusion body myopathy (IBM2), and have elucidated the underlying pathogenetic mechanisms in these conditions. New diagnostic approaches using magnetic resonance imaging, and a blood-based assay for dysferlin deficiency, have also been reported. SUMMARY: These findings have important implications for future genetic linkage and gene expression studies and for the diagnostic approach to patients with a distal myopathy phenotype. They also hold promise for the eventual development of therapies for this group of disorders.
CONTINUUM Lifelong Learning in Neurology · 2019 · 26 citations
Toxic Myopathies
AbstractPURPOSE OF REVIEW: This article reviews the pathogenesis, clinical features, and management of toxic myopathy related to common medications, critical illness, and illicit substances. RECENT FINDINGS: Muscle symptoms are common among statin users and are usually reversible after discontinuation of the statin; rarely, however, statins trigger an immune-mediated necrotizing myopathy that persists and requires immunomodulatory therapy. Autoantibodies targeting 3-hydroxy-3-methylglutaryl coenzyme A reductase can distinguish the toxic and immune-mediated forms. Immune checkpoint inhibitors, increasingly used in the treatment of advanced cancer, have recently been associated with the development of inflammatory myositis. A reversible mitochondrial myopathy has long been associated with zidovudine, but recent reports elucidate the risk of myopathy with newer antivirals, such as telbivudine and raltegravir. SUMMARY: The medications most commonly associated with myopathy include statins, amiodarone, chloroquine, hydroxychloroquine, colchicine, certain antivirals, and corticosteroids, and myopathy can occur with chronic alcoholism. Certain clinical, electrodiagnostic, and histologic features can aid in early recognition. Stopping the use of the offending agent reverses symptoms in most cases, but specific and timely treatment may be required in cases related to agents that trigger immune-mediated muscle injury.
Long-term Natural History of Pediatric Dominant and Recessive <i>RYR1</i> -Related Myopathy
AbstractBACKGROUND AND OBJECTIVES: -related myopathies. METHODS: -related myopathies seen between 1992-2019 in 2 large UK centers. Patients were identified, and data were collected from individual medical records. RESULTS: -related myopathy, 31 recessive, 6 de novo dominant, and 3 uncertain inheritance. Median age at the first and last appointment was 4.0 and 10.8 years, respectively. Fifteen% of patients older than 2 years never walked (5 recessive, 4 de novo dominant, and 1 dominant patient) and 7% lost ambulation during follow-up. Scoliosis and spinal rigidity were present in 30% and 17% of patients, respectively. Respiratory involvement was observed in 22% of patients, and 12% needed ventilatory support from a median age of 7 years. Feeding difficulties were present in 30% of patients, and 57% of those needed gastrostomy or tube feeding. There were no anesthetic-induced malignant hyperthermia episodes reported in this cohort. We observed a higher prevalence of prenatal/neonatal features in recessive patients, in particular hypotonia and respiratory difficulties. Clinical presentation, respiratory outcomes, and feeding outcomes were consistently more severe at presentation and in the recessive group. Conversely, longitudinal analysis suggested a less progressive course for motor and respiratory function in recessive patients. Annual change in forced vital capacity was -0.2%/year in recessive vs -1.4%/year in dominant patients. DISCUSSION: -related myopathies that may inform management and provide essential milestones for future therapeutic interventions.
Journal of Pediatric Hematology/Oncology · 1995 · 12 citations
&epsiv;-Aminocaproic Acid-Associated Myopathy in a Child
AbstractPURPOSE: A 12-year-old girl developed severe autoimmune thrombocytopenia after a bone marrow transplant for acute lymphoblastic leukemia. RESULTS: Although epsilon-aminocaproic acid helped to control her bleeding, it eventually caused a rare myopathy previously undescribed in a pediatric patient. CONCLUSION: The myopathy resolved when the drug was discontinued and a different antifibrinolytic agent was used.
Journal of Neuromuscular Diseases · 2020 · 3 citations
Identification and Functional Analysis of RYR1 Variants in a Family with a Suspected Myopathy and Associated Malignant Hyperthermia
AbstractBACKGROUND: The ryanodine receptor 1 (RyR1) is a major skeletal muscle calcium release channel located in the sarcoplasmic reticulum and involved in excitation-contraction coupling. Variants in the gene encoding RyR1 have been linked to a range of neuromuscular disorders including myopathies and malignant hyperthermia (MH). OBJECTIVE: We have identified three RYR1 variants (c.1983 G>A, p.Trp661*; c.7025A>G, p.Asn2342Ser and c.2447 C>T, p.Pro816Leu) in a family with a suspected myopathy and associated malignant hyperthermia susceptibility. We used calcium release assays to functionally characterise these variants in a recombinant system. METHODS: Site-directed mutagenesis was used to introduce each variant separately into the human RYR1 cDNA. HEK293-T cells were transfected with the recombinant constructs and calcium release assays were carried out using 4-chloro-m-cresol (4-CmC) as the RyR1 agonist to investigate the functional consequences of each variant. RESULTS: RYR1 c.1983 G>A, p.Trp661* resulted in a non-functional channel, c.7025A>G, p.Asn2342Ser in a hypersensitive channel and c.2447 C>T, p.Pro816Leu in a hypersensitive channel at higher concentrations of 4-CmC. CONCLUSIONS: The p.Trp661* RYR1 variant should be considered as a risk factor for myopathies. The p.Asn2342Ser RYR1 variant, when expressed as a compound heterozygote with a nonsense mutation on the second allele, is likely to result in MH-susceptibility. The role of the p.Pro816Leu variant in MH remains unclear.
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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