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Targeting Pathogenic Lafora Bodies in Lafora Disease Using an Antibody-Enzyme Fusion.

Authors
  • Brewer, M Kathryn1
  • Uittenbogaard, Annette1
  • Austin, Grant L1
  • Segvich, Dyann M2
  • DePaoli-Roach, Anna3
  • Roach, Peter J3
  • McCarthy, John J4
  • Simmons, Zoe R1
  • Brandon, Jason A4
  • Zhou, Zhengqiu1
  • Zeller, Jill5
  • Young, Lyndsay E A1
  • Sun, Ramon C1
  • Pauly, James R6
  • Aziz, Nadine M7
  • Hodges, Bradley L7
  • McKnight, Tracy R7
  • Armstrong, Dustin D7
  • Gentry, Matthew S8
  • 1 Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
  • 2 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. , (India)
  • 3 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Lafora Epilepsy Cure Initiative, University of Kentucky College of Medicine, Lexington, KY 40536, USA. , (India)
  • 4 Department of Physiology, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
  • 5 Northern Biomedical Research, Spring Lake, MI 49456, USA.
  • 6 Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
  • 7 Valerion Therapeutics, Concord, MA 01742, USA.
  • 8 Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY 40536, USA; Lafora Epilepsy Cure Initiative, University of Kentucky College of Medicine, Lexington, KY 40536, USA; University of Kentucky Epilepsy & Brain Metabolism Alliance, University of Kentucky College of Medicine, Lexington, KY 40536, USA. Electronic address: [email protected]
Type
Published Article
Journal
Cell metabolism
Publication Date
Oct 01, 2019
Volume
30
Issue
4
Identifiers
DOI: 10.1016/j.cmet.2019.07.002
PMID: 31353261
Source
Medline
Keywords
Language
English
License
Unknown

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.

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