DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for nemaline myopathy 5 — 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 moduleNemaline myopathy 5 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 nemaline myopathy 5 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
Nemaline myopathy affects 1 in 50,000 live births, with prevalence as high as 1 in 20,000 in certain populations. By 2013, pathogenic mutations had been identified in eight genes, with evidence of further genetic heterogeneity; by 2023 more than 15 genes were related to nemaline myopathy, including NEB, ACTA1, TPM3, TPM2, TNNT1, KBTBD13, CFL2, KLHL40, KLHL41, LMOD3, MYO18B, MYPN, RYR3, TTN3, ADSSL1, Filamin C and MYH2. Mutations in NEBULIN account for up to 50% of all cases. The 2013 review noted that current management focuses on supportive treatment and that encouraging advances were emerging for the future, but did not name any specific therapy.
A 2019 paper reported a large-scale chemical screen in a zebrafish model of NEB-related nemaline myopathy and an ENU-based genetic screen in a mouse model of NEB exon 55 deletion, the most common NEBULIN mutation. Neither screen identified a candidate for therapy development. The authors concluded that the results highlight the need to transition from conventional chemical therapeutics to gene-based therapies. A 2018 supplementary file for a study of therapies in a novel nebulin nemaline myopathy model reported testing of taurine, L-carnitine and creatine in wildtype zebrafish, with toxicity analyses provided, and the title of the main paper states a lack of efficacy.
A 2019 review of toxic myopathies noted that muscle symptoms are common among statin users and usually reversible after discontinuation, and that statins can rarely trigger an immune-mediated necrotizing myopathy requiring immunomodulatory therapy. It also noted that immune checkpoint inhibitors have been associated with inflammatory myositis, and that a reversible mitochondrial myopathy has been associated with zidovudine and with newer antivirals such as telbivudine and raltegravir. That review did not address nemaline myopathy. A 2023 study characterised Brazilian patients with nemaline myopathy clinically and by muscle imaging and molecular analysis, but no therapy was tested.
What is still missing is any therapy that has shown efficacy in a preclinical model of nemaline myopathy, let alone in a clinical trial. The largest genetic screens in zebrafish and mouse models of the most common NEBULIN mutation failed to find any candidate compound. Funding for gene-based approaches, better patient stratification by genotype, and trial designs that can detect benefit in a rare, heterogeneous disease are all lacking.
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 Neurology · 2013 · 82 citations
Recent advances in nemaline myopathy
AbstractPURPOSE OF REVIEW: This article reviews recent advances in the understanding of nemaline myopathy, with a focus on the genetic basis of the disorder, histology, and pathogenesis. RECENT FINDINGS: Pathogenic mutations have been identified in eight genes and there is evidence of further genetic heterogeneity in nemaline myopathy. Clinical presentation, histological features on skeletal muscle biopsy, and pattern of changes on muscle MRI may guide prioritization of molecular genetic testing. It is anticipated that use of new technologies such as whole exome sequencing and comparative genomic hybridization will increase the number of genes associated with nemaline myopathy and the proportion of patients in whom the genetic basis of the disorder is identified. Single fiber studies and animal models continue to add to understanding of the pathogenesis of this disorder. Current management focuses on supportive treatment; however, encouraging advances are emerging for the future. SUMMARY: Recent advances in understanding of nemaline myopathy have important implications for clinical practice and for genetic diagnosis of patients with nemaline myopathy.
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.
Failure to identify modifiers of <i>NEBULIN</i> related nemaline myopathy in two pre-clinical models of the disease
AbstractNemaline myopathy is a rare neuromuscular disorder that affects 1 in 50,000 live births, with prevalence as high as 1 in 20,000 in certain populations. 13 genes have been linked to nemaline myopathy, all of which are associated with the thin filament of the muscle sarcomere. Of the 13 associated genes, mutations in NEBULIN accounts for up to 50% of all cases. Currently, the disease is incompletely understood and there are no available therapeutics for patients. To address this urgent need for effective treatments for patients affected by NM, we conducted a large scale chemical screen in a zebrafish model of NEB related nemaline myopathy and a ENU based genetic screen in a mouse model of NEB exon 55 deletion, the most common NEBULIN mutation in nemaline myopathy patients. Neither screen was able to identify a candidate for therapy development, highlighting the need to transition from conventional chemical therapeutics to gene-based therapies for the treatment of nemaline myopathy.
INDIGO (University of Illinois at Chicago) · 2018 · 0 citations · open access
Additional file 1: of Testing of therapies in a novel nebulin nemaline myopathy model demonstrate a lack of efficacy
AbstractSupplementary data for Testing of therapies in a novel nebulin nemaline myopathy model demonstrates and lack of efficacy. Figure S1: Characterisation of Tg(neb-/-; Lifeact-eGFP) fish. Figure S2-S4: Toxicity analyses for treatment of wildtype zebrafish with taurine, L-carnitine and creatine. Figure S5-S6: Quantification of distance travelled and average speed at 6 dpf. Figure S7: Quantification of the phenotypic severity at 6 dpf. Figure S8: Characterisation of facial muscles at 6 dpf. (PDF 7847 kb)
Arquivos de Neuro-Psiquiatria · 2023 · 0 citations · open access
Nemaline myopathy in Brazilian patients: clinical, muscle imaging and molecular characterization
AbstractBackground: Nemaline myopathy (NM) is one of the most common structural congenital myopathies, with a significant clinical and genetic heterogeneity. Nowadays, more than 15 genes are related to NM, including TPM3, NEB, ACTA1, TPM2, TNNT1, KBTBD13, CFL2 (COFILIN2), KLHL40, KLHL41, LMOD3, MYO18B, MYPN, RYR3, TTN3, ADSSL1, Filamin C and MYH2. Most of these genes encode structural or regulatory proteins associated with the thin filament in the skeletal muscle fiber. NM is considered a rare condition and there are no national studies with a large choort of Brazilian nemaline patients.
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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