ArticleNeurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics2022
AAV-Mediated Artificial miRNA Reduces Pathogenic Polyglucosan Bodies and Neuroinflammation in Adult Polyglucosan Body and Lafora Disease Mouse Models.
Article in Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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24 citing papers in PubMed, 31 citations in OpenAlex.
- AAV Vector-Mediated Modulation of Signaling Pathways in Neurological Disorders: Insights From Cellular, Animal, and Human Studies.Cell biochemistry and function · 2026Review
- Glycogen and Glycosylation: Friends or Foes?Biomolecules · 2026Review
- Unifying the Communities of Early-Onset Glycogen Storage Disease Type IV and Adult Polyglucosan Body Disease Through a Genetic Prevalence Study ofJIMD reports · 2026Article
- Lafora disease gene therapy: EPM2A but not EPM2B overexpression results in Lafora body formation.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Article
- Advances in gene therapy for Lafora disease: Intravenous recombinant adeno-associated virus-mediated delivery of EPM2A and EPM2B genes.Clinical and translational medicine · 2025Article
- Autosomal Recessive Cerebellar Ataxias: Translating Genes to Therapies.Annals of neurology · 2025Review
- Splice-modulating antisense oligonucleotides targeting a pathogenic intronic variant in adult polyglucosan body disease correct mis-splicing and restore enzyme activity in patient cells.Nucleic acids research · 2025Article
- Article
- Clinical genetic analysis of an adult polyglucosan body disease (APBD) family caused by the compound heterozygous variant ofFrontiers in genetics · 2025Article
- Progressive liver disease and dysregulated glycogen metabolism in murine GSD IX γ2 models human disease.Molecular genetics and metabolism · 2024Article
- Neurological glycogen storage diseases and emerging therapeutics.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2024Review
- Gene therapy for Lafora disease in the Epm2aMolecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Clinicopathologic Dissociation: Robust Lafora Body Accumulation in Malin KO Mice Without Observable Changes in Home-Cage Behavior.The Journal of comparative neurology · 2024Article
- Beneficial Effect of Fingolimod in a Lafora Disease Mouse Model by Preventing Reactive Astrogliosis-Derived Neuroinflammation and Brain Infiltration of T-lymphocytes.Molecular neurobiology · 2024Article
- Natural history study of hepatic glycogen storage disease type IV and comparison to Gbe1ys/ys model.JCI insight · 2024Article
- The multifaceted roles of the brain glycogen.Journal of neurochemistry · 2024Review
- Myofiber-type-dependent 'boulder' or 'multitudinous pebble' formations across distinct amylopectinoses.Acta neuropathologica · 2024Article
- Lafora progressive myoclonus epilepsy: Disease mechanism and therapeutic attempts.Journal of biosciences · 2024Review
- Gys1 Antisense Therapy Prevents Disease-Driving Aggregates and Epileptiform Discharges in a Lafora Disease Mouse Model.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2023Article
- Deciphering the Polyglucosan Accumulation Present in Lafora Disease Using an Astrocytic Cellular Model.International journal of molecular sciences · 2023Article
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Abstract
Adult polyglucosan body disease (APBD) and Lafora disease (LD) are autosomal recessive glycogen storage neurological disorders. APBD is caused by mutations in the glycogen branching enzyme (GBE1) gene and is characterized by progressive upper and lower motor neuron dysfunction and premature death. LD is a fatal progressive myoclonus epilepsy caused by loss of function mutations in the EPM2A or EPM2B gene. These clinically distinct neurogenetic diseases share a common pathology. This consists of time-dependent formation, precipitation, and accumulation of an abnormal form of glycogen (polyglucosan) into gradually enlarging inclusions, polyglucosan bodies (PBs) in ever-increasing numbers of neurons and astrocytes. The growth and spread of PBs are followed by astrogliosis, microgliosis, and neurodegeneration. The key defect in polyglucosans is that their glucan branches are longer than those of normal glycogen, which prevents them from remaining in solution. Since the lengths of glycogen branches are determined by the enzyme glycogen synthase, we hypothesized that downregulating this enzyme could prevent or hinder the generation of the pathogenic PBs. Here, we pursued an adeno-associated virus vector (AAV) mediated RNA-interference (RNAi) strategy. This approach resulted in approximately 15% reduction of glycogen synthase mRNA and an approximately 40% reduction of PBs across the brain in the APBD and both LD mouse models. This was accompanied by improvements in early neuroinflammatory markers of disease. This work represents proof of principle toward developing a single lifetime dose therapy for two fatal neurological diseases: APBD and LD. The approach is likely applicable to other severe and common diseases of glycogen storage.
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