1. Targeting Pathogenic Lafora Bodies in Lafora Disease Using an Antibody-Enzyme Fusion.
- Author
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Brewer MK, Uittenbogaard A, Austin GL, Segvich DM, DePaoli-Roach A, Roach PJ, McCarthy JJ, Simmons ZR, Brandon JA, Zhou Z, Zeller J, Young LEA, Sun RC, Pauly JR, Aziz NM, Hodges BL, McKnight TR, Armstrong DD, and Gentry MS
- Subjects
- Animals, Brain pathology, Disease Models, Animal, HEK293 Cells, Humans, Immunoglobulin G therapeutic use, Mice, Mice, Inbred C57BL, Pancreatic alpha-Amylases therapeutic use, Rats, Recombinant Fusion Proteins therapeutic use, Brain drug effects, Drug Discovery, Inclusion Bodies drug effects, Lafora Disease therapy, Pancreatic alpha-Amylases pharmacology, Recombinant Fusion Proteins pharmacology
- Abstract
Lafora disease (LD) is a fatal childhood epilepsy caused by recessive mutations in either the EPM2A or EPM2B gene. A hallmark of LD is the intracellular accumulation of insoluble polysaccharide deposits known as Lafora bodies (LBs) in the brain and other tissues. In LD mouse models, genetic reduction of glycogen synthesis eliminates LB formation and rescues the neurological phenotype. Therefore, LBs have become a therapeutic target for ameliorating LD. Herein, we demonstrate that human pancreatic α-amylase degrades LBs. We fused this amylase to a cell-penetrating antibody fragment, and this antibody-enzyme fusion (VAL-0417) degrades LBs in vitro and dramatically reduces LB loads in vivo in Epm2a
-/- mice. Using metabolomics and multivariate analysis, we demonstrate that VAL-0417 treatment of Epm2a-/- mice reverses the metabolic phenotype to a wild-type profile. VAL-0417 is a promising drug for the treatment of LD and a putative precision therapy platform for intractable epilepsy., (Copyright © 2019 Elsevier Inc. All rights reserved.)- Published
- 2019
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