DeCure for Muscular dystrophy-dystroglycanopathy type B6
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for muscular dystrophy-dystroglycanopathy type B6 — 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 moduleMuscular dystrophy-dystroglycanopathy type B6 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 muscular dystrophy-dystroglycanopathy type b6 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
protein O-linked mannose N-acetylglucosaminyltransferase 1 (beta 1,2-) (POMGNT1) — POMGNT1 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 udpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 5GGI · 2.6 Å · ligand URIDINE-5'-DIPHOSPHATE (UDP). Experimental structure, not a prediction.
What the evidence adds up to
In a 2010 transgenic mouse study, lifelong overexpression of the LARGE glycosyltransferase in skeletal and cardiac muscle produced hyperglycosylation of α-dystroglycan and increased laminin binding. Young mice were indistinguishable from wild-type littermates, and muscle histology remained normal even in older animals. However, older mice developed a loss of force in response to eccentric exercise, though this was subclinical and no pathology was seen in the diaphragm or other muscles. The authors concluded that LARGE upregulation as a therapy for dystroglycanopathies should be safe.
A 2002 review of experimental therapies for muscular dystrophies noted that three clinical trials using pharmacological approaches — anabolic agents and gentamicin — showed very poor or negative results. Other pharmacological strategies, such as upregulation of alternative therapeutic proteins, were still only being researched in mice. The review covered gene therapy, cell therapy, and pharmacological therapy, but no efficient treatment to prevent disability and death existed at that time.
A 2019 review focused on drug repurposing for Duchenne muscular dystrophy stated that two genetic-based therapeutics had been approved for clinical use but their efficacy was still very low. The review described ongoing efforts to target downstream pathogenic effects of dystrophin deficiency using classical pharmacological approaches, and noted that drug repurposing could reduce R&D costs for rare diseases. A 2023 chapter on drug repositioning in muscular dystrophies reiterated that no cure exists, that medications and therapy can only help control symptoms and slow progression, and that effective treatments have yet to be developed despite knowledge of genetic origins and pathophysiological changes.
A 2015 case report described whole exome sequencing identifying a COL6A1 mutation in a Korean family initially diagnosed with limb-girdle muscular dystrophy, which was revised to Bethlem myopathy after the genetic finding prompted re-examination for subtle joint contractures. This report did not address treatment.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
PLoS ONE · 2010 · 45 citations · open access
Transgenic Overexpression of LARGE Induces α-Dystroglycan Hyperglycosylation in Skeletal and Cardiac Muscle
AbstractBACKGROUND: LARGE is one of seven putative or demonstrated glycosyltransferase enzymes defective in a common group of muscular dystrophies with reduced glycosylation of α-dystroglycan. Overexpression of LARGE induces hyperglycosylation of α-dystroglycan in both wild type and in cells from dystroglycanopathy patients, irrespective of their primary gene defect, restoring functional glycosylation. Viral delivery of LARGE to skeletal muscle in animal models of dystroglycanopathy has identical effects in vivo, suggesting that the restoration of functional glycosylation could have therapeutic applications in these disorders. Pharmacological strategies to upregulate Large expression are also being explored. METHODOLOGY/PRINCIPAL FINDINGS: In order to asses the safety and efficacy of long term LARGE over-expression in vivo, we have generated four mouse lines expressing a human LARGE transgene. On observation, LARGE transgenic mice were indistinguishable from the wild type littermates. Tissue analysis from young mice of all four lines showed a variable pattern of transgene expression: highest in skeletal and cardiac muscles, and lower in brain, kidney and liver. Transgene expression in striated muscles correlated with α-dystroglycan hyperglycosylation, as determined by immunoreactivity to antibody IIH6 and increased laminin binding on an overlay assay. Other components of the dystroglycan complex and extracellular matrix ligands were normally expressed, and general muscle histology was indistinguishable from wild type controls. Further detailed muscle physiological analysis demonstrated a loss of force in response to eccentric exercise in the older, but not in the younger mice, suggesting this deficit developed over time. However this remained a subclinical feature as no pathology was observed in older mice in any muscles including the diaphragm, which is sensitive to mechanical load-induced damage. CONCLUSIONS/SIGNIFICANCE: This work shows that potential therapies in the dystroglycanopathies based on LARGE upregulation and α-dystroglycan hyperglycosylation in muscle should be safe.
Current Opinion in Neurology · 2002 · 31 citations
Experimental and therapeutic approaches to muscular dystrophies
AbstractPURPOSE OF REVIEW: Most patients suffering from muscular dystrophies can now obtain a precise diagnosis of their underlying molecular defect, but no efficient treatment to prevent disability and death. This review summarizes recent progress towards developing efficient treatments for these severe diseases. RECENT FINDINGS: Different levels of progress have been achieved in three main approaches: gene therapy, cell therapy and pharmacological therapy. Gene therapy has progressed by improving different vectors for gene delivery. Adenoviruses (mainly high capacity versions) and adeno-associated viruses were the most explored viral vectors. Progress was made in understanding the factors needed for an efficient transfection of muscle. An understanding of protein structure and function in muscular dystrophies has allowed elegant examples of protein engineering as a way of gene therapy. Non-viral vectors for gene transfer, targeted gene modification and transcription modulation have also been explored recently. Cell therapy (myogenic-cell transplantation) progressed in understanding myoblast transplantation in primates for human applications, evaluating protocols for the control of graft rejection, understanding the biology of donor myogenic cells, and searching for alternative sources of donor cells. Three clinical trials using pharmacological approaches (anabolic agents and gentamicin) show very poor or negative results. Other pharmacological approaches (upregulation of alternative therapeutic proteins) are still being researched in mice. SUMMARY: This panoply of experimental approaches covered all the current possibilities of attacking the problem of treating muscular dystrophies. It is expected that one or more will progress to provide efficient tools for the ultimate clinical goal: to prolong function and life in severe muscular dystrophy patients.
International Journal of Molecular Sciences · 2019 · 20 citations · open access
Teaching an Old Molecule New Tricks: Drug Repositioning for Duchenne Muscular Dystrophy
AbstractDuchenne muscular dystrophy (DMD) is one of the most severe forms of inherited muscular dystrophies. The disease is caused by the lack of dystrophin, a structurally essential protein; hence, a definitive cure would necessarily have to pass through some form of gene and/or cell therapy. Cell- and genetic-based therapeutics for DMD have been explored since the 1990s and recently, two of the latter have been approved for clinical use, but their efficacy is still very low. In parallel, there have been great ongoing efforts aimed at targeting the downstream pathogenic effects of dystrophin deficiency using classical pharmacological approaches, with synthetic or biological molecules. However, as it is always the case with rare diseases, R&D costs for new drugs can represent a major hurdle for researchers and patients alike. This problem can be greatly alleviated by experimenting the use of molecules that had originally been developed for different conditions, a process known as drug repurposing or drug repositioning. In this review, we will describe the state of the art of such an approach for DMD, both in the context of clinical trials and pre-clinical studies
Journal of Clinical Neurology · 2015 · 8 citations · open access
Molecular Genetic Diagnosis of a Bethlem Myopathy Family with an Autosomal-Dominant<i>COL6A1</i>Mutation, as Evidenced by Exome Sequencing
AbstractBACKGROUND: We describe herein the application of whole exome sequencing (WES) for the molecular genetic diagnosis of a large Korean family with dominantly inherited myopathy. CASE REPORT: The affected individuals presented with slowly progressive proximal weakness and ankle contracture. They were initially diagnosed with limb-girdle muscular dystrophy (LGMD) based on clinical and pathologic features. However, WES and subsequent capillary sequencing identified a pathogenic splicing-site mutation (c.1056+1G>A) in COL6A1, which was previously reported to be an underlying cause of Bethlem myopathy. After identification of the genetic cause of the disease, careful neurologic examination revealed subtle contracture of the interphalangeal joint in the affected members, which is a characteristic sign of Bethlem myopathy. Therefore, we revised the original diagnosis from LGMD to Bethlem myopathy. CONCLUSIONS: This is the first report of identification of COL6A1-mediated Bethlem myopathy in Korea, and indicates the utility of WES for the diagnosis of muscular dystrophy.
IntechOpen eBooks · 2023 · 0 citations · open access
The Potential Benefits of Drug-Repositioning in Muscular Dystrophies
AbstractMuscular dystrophies (MDs) are a complex group of rare neuromuscular disorders caused by genetic mutations that progressively weaken the muscles, resulting in an increasing level of disability. The underlying cause of these conditions consists of mutations in the genes in charge of a person’s muscle composition and functionality. MD has no cure, but medications and therapy can help control symptoms and slow the disease’s progression. Effective treatments have yet to be developed, despite the identification of the genetic origins and a thorough knowledge of the pathophysiological alterations that these illnesses induce. In this scenario, there is an urgent need for novel therapeutic options for these severe illnesses, and drug repositioning might be one feasible answer. In other words, drug repositioning/repurposing is an accelerated method of developing novel pharmaceuticals since the new indication is based on previously accessible safety, pharmacokinetic, and manufacturing data. This is particularly crucial for individuals with life-threatening illnesses such as MDs, who cannot wait for a conventional medication development cycle. This chapter aims to review the challenges and opportunities of drug-repositioning in a variety of MDs to establish novel treatment approaches for these incurable 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.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
