Treating Lafora Disease with an Antibody-Enzyme Fusion

Le résumé fourni par la source

Abstract Lafora disease (LD) is a horrendous progressive myoclonic epilepsy that strikes healthy teenagers and leads to ever-worsening seizures with no relief from antiepileptic drugs; it then transitions to rapid dementia that ends in death typically after 10 years of onset. LD is the result of mutations in either the EPM2A or EPM2B/NHLRC1 gene that encodes the glycogen phosphatase laforin or the E3 ubiquitin ligase malin, respectively. A hallmark of LD is cytoplasmic, aberrant glycogen-like aggregates called Lafora bodies (LBs); thus, LD is also classified as a glycogen storage disease (GSD). Using LD mouse models, multiple laboratories definitively demonstrated that genetic reduction or elimination of glycogen synthesis decreased LB formation and rescued LD epilepsy, neurodegeneration, and brain inflammation. Thus, LBs are the etiological driver of LD. An antibody-enzyme fusion (AEF) was developed that ablates LBs and normalizes both cell signaling and brain metabolism. This AEF is a promising drug for the treatment of LD and other GSDs as well as a putative therapeutic platform for targeting other neurodegenerative diseases.

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