DeCure for Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2 — 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 (congenital with intellectual disability), type B2 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 (congenital with intellectual disability), type b2 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
The 2007 study of 40 patients with dysferlin gene mutations found that only half presented with the two classic dysferlinopathy phenotypes, Miyoshi myopathy and limb-girdle muscular dystrophy type 2B. The remainder showed unusual presentations: a proximodistal phenotype in 35%, pseudometabolic myopathy in 10%, and asymptomatic hyperCKemia in 5%. The disease could worsen rapidly, and a quarter of patients were initially misdiagnosed with polymyositis. The authors suggested a link between the proximodistal phenotype, inflammation, and severity, concluding that dysferlinopathies range from asymptomatic to severe functional disability.
A 2001 review of congenital muscular dystrophies, which include the dystroglycanopathy type B2 specified in the query, describes them as a heterogeneous group with weakness and dystrophic changes present at birth or in early infancy. The review covers laminin α-2 deficiency, Ullrich congenital muscular dystrophy, fukutin-related proteinopathy, rigid spine syndrome, and glycosylation disorders of α-dystroglycan. The last group is often associated with neuronal migration defects, cerebellar and brainstem abnormalities, and variable ocular anomalies. The review states there are still no curative treatment options for patients with congenital muscular dystrophies, and care is limited to regular follow-up and symptomatic management by a multidisciplinary team.
A 2023 review of drug repositioning in muscular dystrophies notes that these disorders have no cure, and effective treatments have yet to be developed despite knowledge of their genetic origins and pathophysiological changes. It argues that drug repositioning, which uses existing safety and pharmacokinetic data, could accelerate the development of novel therapies for life-threatening illnesses such as muscular dystrophies. The review aims to examine the challenges and opportunities of this approach but does not present any clinical trial results or specific repurposed drugs that have shown efficacy in muscular dystrophy-dystroglycanopathy type B2.
No study has tested a repurposed drug in patients with the specific congenital dystroglycanopathy type B2. What is missing is any clinical trial funding, a trial design that accounts for the phenotypic heterogeneity described in the dysferlin literature, and patient stratification by genetic subtype and disease severity.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Archives of Neurology · 2007 · 265 citations
Phenotypic Study in 40 Patients With Dysferlin Gene Mutations
AbstractOBJECTIVE: To describe the phenotypic spectrum of dysferlin (DYSF) gene mutations (which cause dysferlinopathies, autosomal recessive muscular dystrophies) in patients with a dysferlin protein deficiency. DESIGN: Clinical, biological, and pathological data from 40 patients were reviewed. The diagnosis of dysferlinopathy was based on the absence or strong reduction of dysferlin in muscle, and confirmed by mutational screening of the DYSF gene. SETTING: Two French neuromuscular diseases centers (in Paris and Marseilles). RESULTS: Two main dysferlinopathy phenotypes are well recognized: Miyoshi myopathy and limb-girdle muscular dystrophy type 2B. Typical Miyoshi myopathy and limb-girdle muscular dystrophy type 2B were found in 20 (50%) patients only. Unusual phenotypes included a mixed phenotype, referred to as "proximodistal," combining distal and proximal onset in 14 (35%) patients, pseudometabolic myopathy in 4 (10%), and asymptomatic hyperCKemia (an increased serum creatine kinase level) in 2 (5%). The disease may worsen rapidly, and 10 (25%) patients were initially misdiagnosed as having polymyositis. We suggest a relationship between proximodistal phenotype, inflammation, and severity. CONCLUSION: In addition to typical Miyoshi myopathy and limb-girdle muscular dystrophy type 2B, dysferlinopathies are a clinically heterogeneous group of disorders ranging from asymptomatism to severe functional disability.
Handbook of clinical neurology · 2001 · 0 citations
Towards a Flexible information Retrieval Approach based on the Context
AbstractThe congenital muscular dystrophies are a heterogeneous group of disorders in which weakness and dystrophic pattern on muscle biopsy are present at birth or during the first months of life. This chapter reviews the most common forms of congenital muscular dystrophies, including laminin α-2 (merosin) deficiency, Ullrich congenital muscular dystrophy, fukutin-related proteinopathy, rigid spine syndrome, and glycosylation disorders of α-dystroglycan. The latter group is often associated with neuronal migration defects including lissencephaly, pachygyria, cerebellar and brainstem abnormalities, and variable ocular anomalies. Typical clinical findings and underlying genetic defects are discussed to assist in the differential diagnosis and diagnostic work-up of patients with congenital muscular dystrophies. There are still no curative treatment options for patients with congenital muscular dystrophies but regular follow-up and symptomatic care by a multidisciplinary team considering the peculiarities of each disorder are important to maintain or improve patients' quality of life.
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.
Muscular magnet resonance imaging (M-MRI) in α-Dystroglykanopathies – clinical course of two juvenile patients with LGMD2I and LGMD2M
AbstractIntroduction: α-Dystroglycanopathies are a heterogenous group of neuromuscular disorders caused by a hypoglycosilation of the membrane protein α-dystroglycan. Mutations in the genes FKRP, FCMD, POMT1, POMT2, POMGnT1 and LARGE can cause a highly variable clinical phenotype but also disclose a remarkably disease overlap. The clinical phenotype can range from severe congenital onset with brain malformations (e.g. Fukuyama muscular dystrophy) to relatively milder forms (e.g. LGMD2).
The role of the medaka protein O-mannosyltransferase 2 across tissues, development and dystroglycanopathies
AbstractProtein O-mannosylation is a conserved modification of proteins with the sugar mannose. Defective O-mannosylation of the peripheral membrane protein α-dystroglycan (α-DG) results in a spectrum of congenital diseases called dystroglycanopathies (DGpathies). DGpathies manifest a broad range of symptoms from serious, prenatal changes in the morphology of the brain to adult-onset muscular dystrophy. Consequently, mutations in the genes encoding the protein O-mannosyltransferases 1 and 2 (POMT1/2), which catalyse the first steps of O-mannosylation, cause the most severe forms of DGpathies. Why different organs are distinctly affected in patients with varying grades of DGpathies is not clear. Moreover, the precise contribution of the known substrates of the POMT1-POMT2 complex, α-DG, SUCO and KIAA1549, to the pathology in DGpathies remains ill-defined. Therefore, the aim of this thesis was to resolve the organismal role of the POMT1-POMT2 complex in DGpathies and to disentangle the contributions of its substrates. \n \nTo address these questions, I created a framework for highly efficient base editing to mutate virtually any cytosine or adenine in the teleost fish genome. Using CRISPR/Cas9 and base editors, I established pomt2 DGpathy models in medaka (Oryzias latipes) and characterised these using behavioural, biochemical, histological and transcriptomic analyses. I could show that organs such as the eye and the brain are only affected when POMT-complex function was substantially disrupted. By contrast, the muscles and spine are much more prone to minute changes in the enzymatic properties of the POMTs. Next, I disrupted the POMT-substrates individually using a CRISPR/Cas9 approach. I identified a previously unknown cardiovascular function of α-DG and SUCO, and revealed that SUCO plays an important role in notochord development. Finally, I employed base editing to mutate O-mannosylation glycosites on α-DG (T330) and SUCO (S806 and T811), which partially recapitulated respective loss-of-function phenotypes. With this first-ever evidence for the study of glycosites using base editing in vivo, I demonstrate the feasibility of this new approach to provide functional insights in a developing organism. \n \nFuture studies linking structure-function relationships on the substrate level to tissue-wide developmental consequences in model systems will be instrumental to enable tailored, preclinical drug screens and to provide reliable predictions of disease progressions in DGpathies.
Journal of Neurology Neurosurgery & Psychiatry · 1999 · 0 citations · open access
Congenital Muscular Dystrophies
AbstractCongenital Muscular Dystrophies . Edited by y fukuyama, m osawa, and k saito. (Pp 432, NLG 420.00). Published by Elsevier Science, The Netherlands, 1997. ISBN 0-444-82487-1.
This book describes in detail the clinical features and latest research findings on congenital muscular dystrophy. The book follows on from an International Symposium on Congenital Muscular Dystrophies which was held in Tokyo in July 1994. The book has many positive features but also some less good features, so common in edited multiauthor texts.
On the positive side, the book gives a very comprehensive and authoritative review of the clinical features of the various types of congenital muscular dystrophies. I …
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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