DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for myofibrillar myopathy 3 — 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 moduleMyofibrillar myopathy 3 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 myofibrillar myopathy 3 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
Myofibrillar myopathy 3 is caused by dominant negative mutations in alphaB-crystallin. Two patients with adult-onset muscle weakness carried truncating mutations in the C-terminal region of alphaB-crystallin (464delCT and Q151X). Patient 1 had cervical, limb girdle, and respiratory muscle weakness and died of respiratory failure. Patient 2 had proximal and distal leg muscle weakness. Seven to eight percent of nuclei displayed early apoptotic changes. Immunoblots of muscle showed increased expression of wild-type and reduced expression of the mutant protein, and the mutant protein formed lower than normal molecular weight multimeric complexes with wild type. The authors concluded that mutations in alphaB-crystallin are an infrequent cause of myofibrillar myopathy and that alphaB-crystallin-related myopathies display phenotypic heterogeneity.
A separate investigation of eight patients from four families found expression of alpha, eta, and zeta isoforms of protein kinase C and of interleukin-1beta in abnormal muscle fibres, suggesting these may play a role in pathogenesis. However, a study using the TUNEL method in six muscle biopsy specimens found no evidence of apoptotic myonuclei, and the authors noted that further studies regarding the possible role of mitotic catastrophe are needed. A 2014 report on anaesthetic management of a child with BAG3-myopathy, a severe childhood-onset subtype, reviewed possible susceptibility to malignant hyperthermia, rhabdomyolysis, and sensitivity to anaesthetic agents.
A 2023 thesis stated that myofibrillar myopathies are an inherited progressive muscle wasting disease for which there are currently no available treatments. Through animal models, the thesis identified promising new therapies and established model systems to further investigate this group of diseases. What is still missing is any clinical trial testing a specific compound in patients, adequate funding to move candidate therapies from animal models into human studies, and a clear understanding of which patient subgroups might respond to which intervention given the genetic and phenotypic heterogeneity of the disease.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Annals of Neurology · 2003 · 257 citations
Myofibrillar myopathy caused by novel dominant negative αB‐crystallin mutations
AbstractWe here report the second and third mutations in alphaB-crystallin causing myofibrillar myopathy. Two patients had adult-onset muscle weakness. Patient 1 had cervical, limb girdle, and respiratory muscle weakness and died of respiratory failure. Patient 2 had proximal and distal leg muscle weakness. Both had myopathic electromyogram with abnormal electrical irritability and muscle biopsy findings of myofibrillar myopathy and mild denervation. Myofibrillar disintegration begins at the Z-disk and results in abnormal local expression of desmin, alphaB-crystallin, dystrophin, neural cell adhesion molecule (NCAM), and CDC2 kinase. Seven to 8% of nuclei display early apoptotic changes. Both patients carry a truncating mutation in the C-terminal region of alphaB-crystallin (464delCT in Patient 1 and Q151X in Patient 2) which is crucial for the solubilization and chaperone functions of the molecule. cDNA analysis shows the same mutations and no alternatively spliced transcripts. Immunoblots of muscle demonstrate increased expression of wild-type and reduced expression of the mutant protein. Immunoblots under nondenaturing conditions show that the mutant protein forms lower than normal molecular weight multimeric complexes with wild type. We conclude that (1) despite its reduced expression, the mutant protein exerts a dominant negative effect; (2) mutations in alphaB-crystallin are an infrequent cause of myofibrillar myopathy; (3) alphaB-crystallin-related myopathies display phenotypic heterogeneity.
Expression of protein kinase C isoforms and interleukin-1β in myofibrillar myopathy
AbstractBACKGROUND: The term myofibrillar myopathy refers to a rare and clinically heterogeneous group of muscle disorders. The pathogenesis of this myopathy is not well understood. The morphologic hallmark is myofibrillar destruction with abnormal expression of numerous proteins, most consistently of desmin. METHODS: The authors investigated eight patients with myofibrillar myopathy belonging to four families. They studied the role of different protein kinase C isoforms and of interleukin-1beta, a cytokine that might activate protein kinase C and, in addition, mediate myofibrillar proteolysis. RESULTS: Immunohistochemical analysis showed the expression of alpha, eta, and zeta isoforms of protein kinase C and of interleukin-1beta in abnormal muscle fibers. Immunoblots confirmed the immunohistochemical data and revealed the absence of protein kinase C delta and epsilon in muscle fibers from patients and controls. CONCLUSIONS: These data suggest that protein kinase C and interleukin-1beta may play a role in the pathogenesis of myofibrillar myopathy.
Myofibrillar myopathy: No evidence of apoptosis by TUNEL
AbstractThe pathogenesis of myofibrillar myopathy (MFM) is not known. Muscle biopsy specimens demonstrate increased expression of cell cycle regulatory proteins as well as the ectopic expression of lamin B and nuclear matrix protein in the cytoplasm, suggesting the possibility of apoptosis. The authors investigated for apoptosis using the TUNEL method in six muscle biopsy specimens from patients with MFM. There was no evidence of apoptotic myonuclei in any of the MFM muscle biopsies. Further studies regarding the pathogenesis of MFM and the possible role of mitotic catastrophe are needed.
Anesthetic considerations in myofibrillar myopathy
AbstractMyofibrillar myopathy (MFM) is a relatively newly recognized genetic disease that leads to progressive muscle deterioration. MFM has a varied phenotypic presentation and impacts cardiac, skeletal, and smooth muscles. Affected individuals are at increased risk of respiratory failure, significant cardiac conduction abnormalities, cardiomyopathy, and sudden cardiac death. In addition, significant skeletal muscle involvement is common, which may lead to contractures, respiratory insufficiency, and airway compromise as the disease progresses. This study is the first report of anesthetic management of a patient with MFM. We report multiple anesthetic encounters of a child with genetically confirmed BAG3-myopathy, a subtype of MFM with severe childhood disease onset. A review of the anesthetic implications of the disease is provided, with specific exploration of possible susceptibility to malignant hyperthermia, rhabdomyolysis, and sensitivity to other anesthetic agents.
Indian Journal of Rheumatology · 2019 · 2 citations · open access
Drug-Induced Myopathy
AbstractA number of medications, including very commonly used ones, have been described as causing myopathy. Drug-induced myopathy is defined as an acute or subacute adverse effect of a drug on the muscular system, which may range from asymptomatic increase in serum creatine kinase and simple myalgias to life-threatening rhabdomyolysis. It is necessary for the treating physician to recognize these manifestations early and manage promptly; in order to prevent treatment-related morbidity and mortality. A PubMed search was conducted using the MeSH terms “drug AND myopathy” and “drug AND rhabdomyolysis.” The consensus of the authors was sought to finalize a group of 60 articles for further review. With the large number of drugs available to the treating physician today, and the significant drug interactions that can occur, knowledge about the various drugs causing myopathy, their characteristic features if any, and the optimal management of these adverse effects is imperative.
BMJ Case Reports · 2023 · 2 citations · open access
Anaesthetic management of caesarean section in a patient with myofibrillar myopathy
AbstractMyofibrillar myopathies (MFMs) are a group of rare genetic disorders that affect the function of skeletal, cardiac and smooth muscle.MFM exhibits a considerable degree of clinical heterogeneity. In numerous instances of MFM, muscle weakness is the predominant manifestation. Certain MFM subtypes are distinguished by respiratory and cardiac impairment.There is little information available about anaesthetic management in MFM, and even less is known about obstetric anaesthesia.A successful case of a patient with MFM undergoing a caesarean section under combined neuraxial anaesthesia is reported. The patient experienced no complications, and functional recovery was swift.
Exploring therapeutic compounds to treat myofibrillar myopathies
AbstractMyofibrillar myopathies are an inherited progressive muscle wasting disease for which there are currently no available treatments. Through the use of animal models, this thesis identified promising new therapies and established model systems to further investigate this group of diseases.
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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