DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for neuromuscular junction disease — screening already-approved drugs against its 30-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleNeuromuscular junction disease maps to a 30-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 neuromuscular junction 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
potassium voltage-gated channel subfamily C member 1 (KCNC1) — KCNC1 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 5rdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8QUD · 2.5 Å · ligand (5R)-5-ethyl-3-(6-spiro[2H-1-benzofuran-3,1'-cyclopropane]-4-yloxypyridin-3-yl)imidazolidine-2,4-dione (WY0). Experimental structure, not a prediction.
What the evidence adds up to
In 1991, a study of critically ill patients who developed severe weakness after discontinuation of neuromuscular junction blocking agents found that all had pronounced weakness without sensory loss. Electrodiagnostic studies and muscle pathology were consistent with failed neuromuscular transmission. No single disorder or medication was common to all patients. Recovery of strength often took several months, and most patients were slow to wean from mechanical ventilation. The authors concluded that the use of these agents may lead to neurogenic atrophy.
Spinal muscular atrophy, a recessive autosomal neuromuscular disease and the most common fatal paediatric pathology, involves dramatic alterations at the neuromuscular junction, including immaturity, denervation and neurofilament accumulation, associated with impaired synaptic function. A 2016 review noted that these abnormalities may have a detrimental effect on motor neuron survival and that the neuromuscular junction could be an important target for counteracting pathology progression. Congenital myasthenic syndromes are caused by mutations in genes encoding proteins essential for neuromuscular transmission. A 2014 review reported that mutations in lipoprotein-like receptor 4 have now been described, and that the use of salbutamol and ephedrine, alone or combined with pyridostigmine or 3,4-DAP, is increasingly reported in different subtypes with significant benefit.
A 2014 study used an adenovirus vector to deliver the DOK7 gene to mouse models of two distinct neuromuscular disorders. The therapy enlarged the neuromuscular junction, improved motor activity and extended life span in the mice. A 2023 review noted that most existing treatments for neurodegenerative diseases only address symptoms, and that individuals with these diseases have a shorter life expectancy. The review considered it significant that most neurodegenerative disorders lead to health complications with high mortality rates, even if not all are immediately fatal.
What is still missing is evidence from adequately powered human trials, particularly for gene therapy approaches that have only been tested in mice. The heterogeneity of congenital myasthenic syndromes and the lack of a common mechanism in prolonged paralysis after neuromuscular blocking agents mean that patient stratification remains a challenge. Funding for large-scale, long-term studies of neuromuscular junction repair in human disease is 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.
Critical Care Medicine · 1991 · 175 citations
Prolonged paralysis after treatment with neuromuscular junction blocking agents
AbstractOBJECTIVES: Previous reports have described prolonged paralysis after treatment with neuromuscular junction blocking agents in critically ill patients. The purpose of this study was to further describe a group of patients who developed prolonged weakness after treatment with these agents. DESIGN: Clinical information, electrodiagnostic and muscle pathology results are described in this group of patients. Clinical information includes diagnoses, dosage of neuromuscular junction blocker, other medications affecting the neuromuscular system, and neuromuscular examination and clinical course. SETTING: All patients were seen in the ICUs of three local hospitals. PATIENTS: Included were critically ill patients with a variety of diagnoses, all of whom developed severe weakness after discontinuation of neuromuscular junction blocking agents. INTERVENTIONS: Electrodiagnostic studies and muscle biopsies were performed on several of the patients. MEASUREMENTS AND MAIN RESULTS: All patients had pronounced weakness without sensory loss. Electrodiagnostic and muscle pathology findings were consistent with failed neuromuscular transmission. Although many patients had disorders or were taking medications that can injure the neuromuscular system, no disorder or medication was common to all. Recovery of strength often took several months and most patients were slow to wean from mechanical ventilator support. CONCLUSIONS: Although alternative explanations cannot be excluded with certainty, the use of neuromuscular junction blocking agents may lead to neurogenic atrophy and care must be taken when using them.
Frontiers in Neuroanatomy · 2016 · 79 citations · open access
Neuromuscular Junctions as Key Contributors and Therapeutic Targets in Spinal Muscular Atrophy
AbstractSpinal muscular atrophy (SMA) is a recessive autosomal neuromuscular disease, representing the most common fatal pediatric pathology. Even though, classically and in a simplistic way, it is categorized as a motor neuron (MN) disease, there is an increasing general consensus that its pathogenesis is more complex than expected. In particular, neuromuscular junctions (NMJs) are affected by dramatic alterations, including immaturity, denervation and neurofilament accumulation, associated to impaired synaptic functions: these abnormalities may in turn have a detrimental effect on MN survival. Here, we provide a description of NMJ development/maintenance/maturation in physiological conditions and in SMA, focusing on pivotal molecules and on the time-course of pathological events. Moreover, since NMJs could represent an important target to be exploited for counteracting the pathology progression, we also describe several therapeutic strategies that, directly or indirectly, aim at NMJs.
Current Opinion in Neurology · 2014 · 68 citations
Congenital myasthenic syndromes and the neuromuscular junction
AbstractPURPOSE OF REVIEW: Congenital myasthenic syndromes (CMS) are a group of heterogeneous inherited disorders caused by mutations in genes encoding proteins essential for the integrity of neuromuscular transmission. This review updates the reader on the new mutations of known CMS genes, new causative genes and the treatment strategies for these increasingly heterogeneous disorders. It also provides a brief summary of the congenital myopathies with myasthenic features. RECENT FINDINGS: The discovery of causative genes encoding for ubiquitously expressed and extrajunctional molecules has changed our previous view of congenital myasthenia. Mutations associated with the N-glycosylation pathway and in the family of serine peptidases have shown that abnormalities in the post-translational modification of proteins can produce defects at the human neuromuscular junction. However, mutations in lipoprotein-like receptor 4, a long-time candidate gene for congenital myasthenia, have now been described and a new pathogenic splicing mutation in the nonfunctional exon of CHRNA1 has been reported. The use of salbutamol and ephedrine alone or combined with pyridostigmine or 3,4-DAP is increasingly being reported in different CMS subtypes with significant benefit. SUMMARY: Recent studies of the CMS illustrate the increasing complexity of the genetics, pathophysiological mechanisms and therapy of impaired synaptic transmission at the neuromuscular junction.
IntechOpen eBooks · 2023 · 0 citations · open access
Neurodegeneracy
AbstractDespite its vulnerability to neurodegenerative diseases, the neuromuscular junction has developed powerful ways to withstand injury and regenerate. Individuals with neurodegenerative diseases have a shorter life expectancy. Most existing treatments for neurodegenerative diseases only address symptoms. In order to limit the harmful effects, it is important to develop successful therapies to setback the symptoms of these debilitating diseases. Though some neurodegenerative disorders are fatal, most lead to health complications that are associated with high mortality rates. Although this difference might be a matter of semantics, we consider it significant, not only for managing the patient but also for our understanding of the actual consequences of the neurodegenerative process.
AbstractNeuromuscular Disease
Voluntary movement requires a molecular conversation between nerves and muscles. This conversation occurs at the neuromuscular junction, a structure where nerves and muscle physically connect. People with diseases characterized by muscle weakness have aberrantly small neuromuscular junctions. Arimura et al. used gene therapy to enlarge the neuromuscular junction, which made muscles stronger. Studying mouse models of two distinct neuromuscular disorders, they used an adenovirus vector to deliver DOK7 , a gene required for formation of the neuromuscular junction. The therapy improved the mice's motor activity and life span.
Science , this issue p. [1505][1]
[1]: /lookup/doi/10.1126/science.1250744
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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