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

M Kathryn Brewer; Annette Uittenbogaard; Grant L Austin; Dyann M Segvich; Anna DePaoli-Roach; Peter J Roach; John J McCarthy; Zoe R Simmons; Jason A Brandon; Zhengqiu Zhou; Jill Zeller; Lyndsay E A Young; Ramon C Sun; James R Pauly; Nadine M Aziz; Bradley L Hodges; Tracy R McKnight; Dustin D Armstrong; Matthew S Gentry

doi:10.1016/j.cmet.2019.07.002

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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.

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. This record was last updated on 09/12/2020 and may not reflect the most current and accurate biomedical/scientific data available from NLM. The corresponding record at NLM can be accessed at https://www.ncbi.nlm.nih.gov/pubmed/31353261

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Abstract

Targeting pathogenic Lafora bodies in Lafora disease using an antibody-enzyme fusion

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