DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for muscular dystrophy-dystroglycanopathy — screening already-approved drugs against its 2-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 maps to a 2-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 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
fukutin related protein (FKRP) — FKRP 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 cdpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6KAJ · 2.2249 Å · ligand CYTIDINE-5'-DIPHOSPHATE (CDP). Experimental structure, not a prediction.
What the evidence adds up to
In a 2010 study, transgenic mice overexpressing human LARGE showed α-dystroglycan hyperglycosylation in skeletal and cardiac muscle, with increased laminin binding and normal muscle histology in young animals. Older mice developed a loss of force in response to eccentric exercise, but this remained subclinical — no pathology was seen even in the diaphragm. The authors concluded that LARGE upregulation in muscle should be safe.
A 2021 review notes that more than 30 years after the first protein involved in muscular dystrophy was identified, there is still no effective treatment for these disorders. It summarises a range of experimental gene therapies and animal models but does not report any clinical success.
A separate 2021 study tested AAV-mediated LARGE1 gene transfer in myd mice, which lack Large1 and have severe muscular dystrophy with 50% survival at 35 weeks. In mice older than 34 weeks with advanced disease, systemic delivery of AAV Large1 restored matriglycan expression, attenuated skeletal muscle pathology, improved motor and respiratory function, normalised systemic metabolism, and dramatically extended survival. The authors state that skeletal muscle function can be restored and survival greatly improved even after the onset of severe pathophysiology in this mouse model.
What is still missing is any human trial data — all results come from transgenic or viral-vector mouse experiments. The 2010 safety study used only 4 transgenic lines and did not test the vector that later showed efficacy in the myd mouse. No information is available on delivery, dosing, or immune response in patients, and the heterogeneity of the 18 known human dystroglycanopathy genes means that a single-gene approach may not apply to all forms.
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.
Journal of Inherited Metabolic Disease · 2004 · 31 citations · open access
Congenital disorders of glycosylation (CDG): Update and new developments
AbstractAfter a brief overview on CDG, this workshop concentrated on the experience with (mostly) known CDG in a European country (the Czech Republic) and on the Australasian experience, on recent developments regarding congenital muscular dystrophies due to O-mannoslyglycan assembly defects, and on new presentations of CDG. It was concluded that we are still at the beginning of 'explosive' research on CDG and that we need to apply new and known technologies to the diagnosis, understanding of pathophysiology, and treatment of CDG.
New England Journal of Medicine · 1965 · 24 citations
Ineffective Treatment of Muscular Dystrophy with an Anabolic Steroid and Other Measures
AbstractTHROUGHOUT the years many agents have been tested for their therapeutic benefit in muscular dystrophy, a relentlessly progressive disease. Eventually, all have been found to be ineffective after careful evaluation, including a variety of anabolic hormones.1 2 3 4 5 6 7 8 More recently Dowben9 has presented preliminary evidence that patients with muscular dystrophy showed significant "improvement" when treated by a program consisting of the anabolic steroid, 1-methyl-Δ1 androstenolone acetate,ǁ digitoxin and exercise.The purpose of this report is to re-evaluate such a therapeutic program in muscular dystrophy when the drugs are used singly, in combination and with or without exercise. Objective serial measurements were made . . .
Experimental and Therapeutic Medicine · 2021 · 14 citations · open access
Muscular dystrophy: Experimental animal models and therapeutic approaches (Review)
AbstractThe muscular dystrophies are a heterogeneous group of genetically inherited diseases characterized by muscle weakness and progressive wasting, which can cause premature death in severe forms. Although >30 years have passed since the identification of the first protein involved in a type of muscular dystrophy, there is no effective treatment for these disabling disorders. In the last decade, several novel therapeutic approaches have been developed and investigated as promising therapeutic approaches aimed to ameliorate the dystrophic phenotype either by restoring dystrophin expression or by compensating for dystrophin deficiency. Concurrently, with the development of therapeutic approaches, in addition to naturally occurring animal models, a wide range of genetically engineered animal models has been generated. The use of animals as models of muscular dystrophies has greatly improved the understanding of the pathogenicity of these diseases and has proven useful in gene therapy studies. In this review, we summarize these latest innovative therapeutic approaches to muscular dystrophies and the usefulness of the various most common experimental animal models.
AbstractA 12-month clinical study of Duchenne muscular dystrophy was carried out during a double-blind trial of allopurinol therapy. The disease was monitored by assessment of muscle power and function, pulmonary function tests, and electrocardiography. Biochemical assessments were made of plasma creatine kinase, pyruvate kinase, uric acid, and urinary excretion of 3-methylhistidine and creatinine. Allopurinol did not alter the progression of the disease.
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.
Trends in Glycoscience and Glycotechnology · 2021 · 0 citations
Advances in Pathophysiology of Dystroglycanopathies and Its Treatment Strategies
AbstractDystroglycanopathy is a group of muscular dystrophy caused by abnormal glycosylation of dystroglycan. Dystroglycan is a cell membrane receptor of basement membrane molecules and synaptic molecules. The sugar chain abnormalities result in the disruption of dystroglycan-mediated linkage between the basement and cell membrane in the skeletal muscle. The sugar chain structure and modifying enzymes of dystroglycan have recently been identified, and the pathophysiological significance of dystroglycan sugar chains in various tissues has also been clarified. This mini-review introduces the latest findings on the mechanisms of dystroglycanopathy and the development of various treatment strategies.
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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