DeCure for Muscular dystrophy-dystroglycanopathy, type A
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for muscular dystrophy-dystroglycanopathy, type A — screening already-approved drugs against its 8-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 A maps to a 8-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 a 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
dystroglycan 1 (DAG1) — DAG1 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 7E9K · 2.05 Å · ligand URIDINE-5'-DIPHOSPHATE (UDP). Experimental structure, not a prediction.
What the evidence adds up to
In 2010, transgenic mice overexpressing human LARGE in skeletal and cardiac muscle showed α-dystroglycan hyperglycosylation and increased laminin binding. Young mice were indistinguishable from wild-type littermates, and general muscle histology was normal. However, older mice developed a loss of force in response to eccentric exercise, though this remained subclinical and no pathology was seen even in the diaphragm. The authors concluded that LARGE upregulation in muscle should be safe.
A 2021 study tested systemic AAV2/9 delivery of Large1 in myd mice (which lack Large1 and have 50% survivorship at 35 weeks) that were already over 34 weeks old with advanced disease. Treatment restored matriglycan expression, attenuated skeletal muscle pathophysiology, improved motor and respiratory function, normalised systemic metabolism, and dramatically extended survival. The authors stated that skeletal muscle function could be restored and survival greatly improved even after severe pathophysiology had developed.
The broader context is that dystroglycanopathies are a group of congenital muscular dystrophies defined by abnormal O-glycosylation of α-dystroglycan, with at least 18 known causative genes as of 2015, and severity ranging from Walker-Warburg syndrome with brain malformations to adult-onset limb-girdle muscular dystrophy. Reviews from 2012 and 2012 note that pharmacological and gene-based strategies are advancing, with some reaching clinical trials for dystrophinopathies and limb-girdle dystrophies, but no specific drug or trial for dystroglycanopathy type A is described in these abstracts.
What remains missing is any human trial data for this specific subtype, any pharmacological compound that has been tested in patients, and any evidence that LARGE gene therapy or upregulation can be delivered safely and effectively in humans. The mouse data are promising but come from a single genetic model, and the long-term safety of sustained LARGE overexpression in human muscle is unknown. No patient stratification strategy or trial design has been proposed in these abstracts.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Seminars in Neurology · 2012 · 71 citations
The Muscular Dystrophies
AbstractThe muscular dystrophies are disorders of progressive muscular degeneration and weakness. As a group they display clinical heterogeneity that reflects the heterogeneity of molecular mechanisms responsible for them, and range from congenital to adulthood onset. Recent advances in the field include improved methods of diagnosis, continued identification of disease genes, and the development of a unified model of pathogenesis in facioscapulohumeral dystrophy. These advances are reflected in the development of new therapeutic approaches, some of which have already led to clinical trials in the dystrophinopathies and limb-girdle dystrophies.
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 · 2012 · 24 citations
Pharmacological therapies for muscular dystrophies
AbstractPURPOSE OF REVIEW: The study reviews recent advances in pharmacological management of muscular dystrophies. Similarities and differences among the pathophysiology of different forms of muscular dystrophy lead to a broad array of approaches to provide new treatments. RECENT FINDINGS: In this review, we include only those muscular dystrophies for which advances have been published in the past year. This represents the 'advancing edge' of a large body of research over more than 20 years. This runs the gamut of new discoveries in symptomatic management to mutation-specific strategies that attempt to correct the root cause of the disorder. SUMMARY: The field of pharmacological therapies for the muscular dystrophies continues to steadily advance. It is encouraging that research into new therapies is increasingly exploring pharmacological strategies with the potential to ameliorate disease pathology to a clinically significant degree.
Intrafamilial variability in <i>GMPPB</i> -associated dystroglycanopathy: Broadening of the phenotype
AbstractDystroglycanopathies are characterized by deficient O-mannosyl glycosylation of α-dystroglycan (αDG) and represent an expanding genetically, biochemically, and clinically heterogeneous group of muscular dystrophies. Currently, there are 18 known genes leading to forms of α-dystroglycan–related dystrophy (αDG-RD), ranging in severity from a Walker-Warburg phenotype with severe brain malformations and hypotonia to milder childhood- or adult-onset limb-girdle muscular dystrophy (LGMD) phenotypes with or without intellectual disability.1,2
Journal of Inborn Errors of Metabolism and Screening · 2023 · 5 citations · open access
Dystroglycanopathies: Genetic Bases of Muscular Dystrophies Due to Alteration in the O-Glycosylation of α-Dystroglycan
AbstractCongenital muscular dystrophies (CMDs) are inherited, progressive and heterogeneous muscle disorders. A group of CMDs are dystroglycanopathies, also called α-dystroglycanopathies, where there is an abnormal glycosylation of protein α-dystroglycan. Hypoglycosylation of α-DG results in different severities of congenital muscular dystrophies and they present with progressive muscle weakness and loss of motor functions. This article first focuses on the CMDs, their classification according to the observed symptoms or the protein involved in the resulting phenotype. We then focus on dystroglycanopathies, the importance of its correct O-glycosylation of the α-dystroglycan given its important structural function, considering the enzymes involved in said glycosylation and the phenotypes that can result, to finally address current therapeutics for these diseases with the aim of increasing current knowledge.
bioRxiv (Cold Spring Harbor Laboratory) · 2021 · 0 citations · open access
<i>Large1</i> Gene Transfer in Older <i>myd</i> Mice with Severe Muscular Dystrophy Restores Muscle Function and Greatly Improves Survival
AbstractABSTRACT Muscular dystrophy is a progressive and ultimately lethal neuromuscular disease due to lack of therapeutic options that restore muscle function. Gene editing and gene transfer hold great promise as therapies for various neuromuscular diseases when administered prior to the onset of severe clinical symptoms. However, the efficacy of these strategies for restoring neuromuscular function and improving survival in the late stages of muscular dystrophy with severe muscle pathophysiology is unknown. Dystroglycanopathies are muscular dystrophies characterized by extensive skeletal muscle degeneration and, in many cases, are accompanied by eye and brain abnormalities. Thus far, mutations in at least eighteen human genes are known to cause dystroglycanopathies, including those in the like-acetylglucosaminyltransferase-1 ( LARGE1 ) gene. LARGE1 encodes a xylosyl- and glucuronosyltransferase that modifies α-dystroglycan (α-DG) with matriglycan, a linear repeating disaccharide of alternating xylose and glucuronic acid that binds to the laminin G-like domains of extracellular matrix proteins with high affinity. Large myd /Large myd ( myd) mice lack expression of Large1 , and exhibit severe skeletal muscle pathophysiology, impaired mobility, and a drastically reduced lifespan (50% survivorship at 35 weeks of age). Here, we show that systemic delivery of AAV2/9 CMV Large1 (AAV Large1 ) in >34-week-old myd mice with advanced disease restores matriglycan expression, attenuates skeletal muscle pathophysiology, improves motor and respiratory function, and normalizes systemic metabolism, which collectively and dramatically extends survival. Our results demonstrate that in a mouse model of muscular dystrophy, skeletal muscle function can be restored, illustrating its remarkable plasticity, and that survival can be greatly improved even after the onset of severe skeletal muscle pathophysiology.
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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