DeCure for Myopathy, myofibrillar, 13, with rimmed vacuoles
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for myopathy, myofibrillar, 13, with rimmed vacuoles — 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 moduleMyopathy, myofibrillar, 13, with rimmed vacuoles 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 myopathy, myofibrillar, 13, with rimmed vacuoles 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
heat shock protein family B (small) member 8 (HSPB8) — HSPB8 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 apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8S7A · 1.951 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
A long-term follow-up study from 1989 of patients with familial distal myopathy and rimmed vacuoles reported an extremely poor prognosis for daily life. The initial symptom, appearing in early adulthood, was muscular wasting and weakness in the legs, especially distal muscles. In the advanced stage, severe generalised skeletal muscle involvement was seen, with sparing of facial, extraocular, bulbar, intercostal and diaphragm muscles. The authors noted a considerable female preponderance, with a female-to-male ratio of 2:1, and stated the disease was probably inherited as an autosomal recessive trait. A separate 1988 case report described a 26-year-old man with a predominantly distal myopathy and complete heart block; his muscle biopsy showed numerous vacuoles containing membranous whorls, but no filamentous inclusions.
A 2002 study identified a missense mutation in the myosin heavy chain IIa gene (MYH2) causing an autosomal dominant myopathy. In nine muscle specimens from six individuals carrying the mutation, young patients with muscle weakness and minor pathological changes expressed MyHC IIa at undetectable levels. Adults with a progressive clinical course and dystrophic changes expressed MyHC IIa at high levels, and its expression was a consistent finding in muscle fibres with rimmed vacuoles. The authors concluded that defects in MyHC may lead not only to muscle weakness but also to muscle degeneration.
A 2003 report described a family with two individuals who had clinical distal myopathy with rimmed vacuoles and a compound heterozygous mutation in the GNE gene, characterised by V572L and I472T. These patients also showed inflammatory changes in the connective tissue between muscle fibres, which the authors noted was not typical for DMRV. A 2018 study of three unrelated probands with late-onset predominant distal myopathy found a combination of a heterozygous pathogenic mutation in SQSTM1 (c.1175C>T, p.Pro392Leu) and a heterozygous variant in TIA1 (c.1070A>G, p.Asn357Ser) in all three. Two probands had a distal myopathy with rimmed vacuoles; the third had myofibrillar myopathy presenting with hypercapnic respiratory insufficiency and distal weakness. Affected family members carried both variants, while unaffected members carried one or none. The authors suggested the TIA1 variant may be a modifier of the SQSTM1 mutation.
A 1997 review noted that sporadic inclusion body myositis is a frequent acquired adult-onset vacuolar myopathy, but that a uniform and sustained therapeutic response to immunomodulatory agents had not been achieved. The same review stated that hereditary noninflammatory rimmed vacuolar myopathies were being redefined with molecular genetics. What remains missing is a clear understanding of how the various genetic defects — in MYH2, GNE, SQSTM1, and TIA1 — produce the shared pathological feature of rimmed vacuoles, and whether any of these pathways are druggable. No clinical trial data exist for any drug in this specific group of myopathies, and no patient stratification strategy has been tested.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Brain · 1989 · 71 citations · open access
DISTAL MYOPATHY WITH RIMMED VACUOLE FORMATION
AbstractA long-term follow-up study of patients with familial distal myopathy with rimmed vacuole formation and a review of the literature indicates that the prognosis of the disorder was extremely poor as to daily life. Although the initial symptom appearing in early adulthood was muscular wasting and weakness in the legs, especially the distal muscles, severe generalized skeletal muscle involvement with sparing of the facial, extraocular, bulbar, intercostal and diaphragm muscles was recognized in the advanced stage. The disease is probably inherited as an autosomal recessive trait, while there is a considerable female preponderance, the female-to-male ratio being 2:1. The disorder is distinguishable from various types of distal myopathy on the basis of clinical and pathological findings, and other myopathies with rimmed vacuole formation, including inclusion body myositis, from a prognostic viewpoint.
Myosin heavy chain IIa gene mutation E706K is pathogenic and its expression increases with age
AbstractBACKGROUND: The authors recently described a new autosomal dominant myopathy (OMIM 605637 inclusion body myopathy 3) associated with a missense mutation in the myosin heavy chain (MyHC) IIa gene (MyHC IIa, Human Gene Map [HGM] locus MYH2). Young patients showed minor changes in their muscle biopsies, although dystrophic alterations and rimmed vacuoles with 15- to 20-nm tubulofilaments identical to those in sporadic inclusion body myositis (s-IBM) were observed in some of the adult (especially older) patients. The current study was undertaken to investigate the relation between expression of the mutant MyHC IIa and pathologic changes in muscle. METHODS: The expression of MyHC IIa in nine muscle specimens from six individuals carrying the mutation was analyzed by immunohistochemistry, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and a new reverse transcriptase--PCR method to measure the relative abundance of the various MyHC transcripts. RESULTS: Young patients with muscle weakness and minor pathologic changes in muscle expressed MyHC IIa at undetectable levels. MyHC IIa was expressed at high levels in adults with a progressive clinical course and dystrophic muscle changes. In these cases, a large number of muscle fibers were hybrids with expression of more than one MyHC isoform. Both MyHC IIa alleles were equally expressed. The relative level of MyHC IIa transcripts exceeded that of the corresponding protein, indicating an increased turnover of mutated protein. MyHC IIa expression was a consistent finding in muscle fibers with rimmed vacuoles. CONCLUSIONS: The clear correlation between pathologic changes and expression of MyHC IIa indicates that defects in MyHC may lead not only to muscle weakness but also to muscle degeneration. The consistent expression of MyHC IIa in muscle fibers with rimmed vacuoles indicates that the breakdown of sarcomeric proteins is a key element in the pathogenesis of rimmed vacuoles of s-IBM type.
<i>GNE</i> mutations causing distal myopathy with rimmed vacuoles with inflammation
AbstractThe authors describe a family in which two individuals have clinical distal myopathy with rimmed vacuoles (DMRV). While the clinical and most of the pathologic features in these patients were compatible with a diagnosis of DMRV, the presence of inflammatory changes in the connective tissue between muscle fibers was not. Gene analysis revealed a compound heterozygous mutation in these individuals, characterized by V572L and I472T.
Current Opinion in Neurology · 1997 · 43 citations
Inclusion body myositis and myopathies
AbstractSporadic inclusion body myositis is a frequent, acquired, adult-onset vacuolar myopathy affecting proximal and distal muscles with a distinct, easily identifiable clinical pattern. Although its primary cause is still unknown, autoimmune, viral, and degenerative processes, alone or in combination, are being considered. A uniform and sustained therapeutic response using the currently available immunomodulatory agents has not yet been achieved. Hereditary, inherited noninflammatory rimmed vacuolar myopathies with similar histologic features, collectively called hereditary inclusion body myopathies, are being redefined with the use of molecular genetics. The implications of the recent advances in clinical and basic sciences are discussed in the present review.
Frontiers in Neurology · 2018 · 39 citations · open access
Myopathy With SQSTM1 and TIA1 Variants: Clinical and Pathological Features
AbstractObjective: To identify the molecular defect of three unrelated individuals with late-onset predominant distal myopathy; to describe the spectrum of phenotype resulting from the contributing role of two variants in genes located on two different chromosomes; and to highlight the under-appreciated complex forms of genetic myopathies. Patients and methods: Clinical and laboratory data of three unrelated probands with predominantly distal weakness manifesting in the 6th-7th decade of life and available affected and unaffected family members were reviewed. NGS panel, whole exome sequencing, and targeted analyses of family members were performed to elucidate the genetic etiology of the myopathy. Results: Genetic analyses detected two contributing variants located on different chromosomes in three unrelated probands: a heterozygous pathogenic mutation in SQSTM1 (c.1175C>T, p.Pro392Leu) and a heterozygous variant in TIA1 (c.1070A>G, p.Asn357Ser). The affected fraternal twin of one proband also carries both variants, while the unaffected family members harbor one or none. Two unrelated probands (family 1, II.3 and family 3, II.1) have a distal myopathy with rimmed vacuoles that manifested with index extensor weakness; the other proband (family 2, I.1) has myofibrillar myopathy manifesting with hypercapnic respiratory insufficiency and distal weakness. Conclusions: The findings indicate that all the affected individuals have a myopathy associated with both variants in SQSTM1 and TIA1, respectively, suggesting that the two variants determine the phenotype and likely functionally interact. We speculate that the TIA1 variant is a modifier of the SQSTM1 mutation. We identify the combination of SQSTM1 and TIA1 variants as a novel genetic defect associated with myofibrillar myopathy, and suggest to consider sequencing both genes in the molecular investigation of myopathy with rimmed vacuoles and myofibrillar myopathy, although additional studies are needed to investigate the digenic nature of the disease.
Distal Vacuolar Myopathy With Complete Heart Block
AbstractWe describe a 26-year-old man with a predominantly distal myopathy and complete heart block. A muscle biopsy specimen demonstrated numerous vacuoles, which, by electron microscopy, contained membranous whorls. Filamentous inclusions characteristic of inclusion body myositis were not seen. It is important to be aware that life-threatening cardiac disease may occur in this setting.
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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