DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for nemaline myopathy 2 — 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 moduleNemaline myopathy 2 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 nemaline myopathy 2 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
actin alpha 1, skeletal muscle (ACTA1) — ACTA1 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 adpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9DUV · 3.3 Å · ligand ADENOSINE-5'-DIPHOSPHATE (ADP). Experimental structure, not a prediction.
What the evidence adds up to
The nemaline myopathies are a group of congenital myopathies defined by muscle weakness and the presence of nemaline rods on muscle biopsy. At least twelve causative genes have been identified, encoding structural or regulatory proteins of the thin filament, and there is evidence of further genetic heterogeneity. Clinical presentation, histological features, and muscle MRI patterns vary widely and may guide genetic testing. Whole exome sequencing and comparative genomic hybridisation are expected to increase the number of associated genes and the proportion of patients with a genetic diagnosis. Current management focuses on supportive treatment.
A 2018 study tested therapies in a novel nebulin nemaline myopathy zebrafish model (Tg(neb-/-; Lifeact-eGFP)). The supplementary data explicitly state that the work demonstrates a lack of efficacy for taurine, L-carnitine, and creatine. The file includes toxicity analyses for these compounds in wildtype zebrafish and quantification of distance travelled, average speed, and phenotypic severity at 6 days post-fertilisation, but no therapeutic benefit is reported.
Two review articles from 2013 and 2021 summarise what is known about pathogenesis from mutations in each causative gene and provide perspectives on pathogenetic mechanisms possibly open to therapeutic modalities. The 2013 review notes that single fiber studies and animal models continue to add to understanding, and that encouraging advances are emerging for the future, but it does not name any specific drug or intervention that has shown efficacy in nemaline myopathy. A separate 2019 review on toxic myopathies discusses medications such as statins, amiodarone, chloroquine, and antivirals, but these are causes of myopathy in other contexts, not treatments for nemaline myopathy. A 2013 review on biological therapy in idiopathic inflammatory myopathies covers immune-mediated diseases distinct from nemaline myopathy.
What is still missing is any clinical trial data for a drug that improves muscle strength or survival in nemaline myopathy patients. The zebrafish model tested three compounds and found no efficacy. No randomised controlled trials in humans are reported in these abstracts. Patient stratification by the specific causative gene mutation may be necessary, but no such stratified trial has been conducted. Funding for preclinical work and for designing trials that account for the genetic and clinical heterogeneity of the disease remains 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.
Neuromuscular Disorders · 2021 · 85 citations · open access
Recent advances in nemaline myopathy
AbstractThe nemaline myopathies constitute a large proportion of the congenital or structural myopathies. Common to all patients is muscle weakness and the presence in the muscle biopsy of nemaline rods. The causative genes are at least twelve, encoding structural or regulatory proteins of the thin filament, and the clinical picture as well as the histological appearance on muscle biopsy vary widely. Here, we suggest a renewed clinical classification to replace the original one, summarise what is known about the pathogenesis from mutations in each causative gene to the forms of nemaline myopathy described to date, and provide perspectives on pathogenetic mechanisms possibly open to therapeutic modalities.
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.
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)
Biological therapy in idiopathic inflammatory myopathies
AbstractIdiopathic inflammatory myopathies are systemic, immune-mediated diseases characterized by proximal, symmetrical, progressive muscle weakness. The aim of this work is to give an overview of the biological therapy used in the treatment of idiopathic inflammatory myopathies. The authors also focus on novel results in the therapy directed against the B- and T-cells. They emphasize the importance of new trials in these diseases which may lead to the introduction of novel therapeutic options in these disorders.
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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