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

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

Lafora disease (LD) is a devastating childhood epilepsy caused by intracellular, aberrant glycogen aggregates called Lafora bodies (LBs) in the brain and other tissues. Herein, Brewer et al. generated a first-in-class antibody-enzyme fusion, VAL-0417, that degrades LBs in vitro and in vivo in a pre-clinical model, showing promise as a LD drug.

Original languageEnglish
Pages (from-to)689-705.e6
JournalCell Metabolism
Volume30
Issue number4
DOIs
StatePublished - Oct 1 2019

Bibliographical note

Funding Information:
We thank Drs. Craig Vander Kooi and Jeffrey Rush of the University of Kentucky (UK) Department of Molecular and Cellular Biochemistry; Deb Ramsdell; and Drs. Beth Goad, Rob Schaffer, and Hal Landy of Valerion Therapeutics for valuable feedback and discussions. We also thank Drs. Berge Minassian and Felix Nitschke for fruitful discussions and recommendations. We appreciate the technical support of Dr. Carole Moncman, Azin Akbari, Nico Briot, the UK Electron Microscopy Core, Dr. Thomas Wilkop and the UK Light Microscopy Core, Dana Napier, and Karrie Jones. We also thank the UK Sanders-Brown Center on Aging and Adam Bachstetter for assistance with slide scanning and Biswa Choudhury and Sulabha Argade for their assistance with HPAEC-PAD experiments (GlycoAnalytics, University of California, San Diego, CA). This work is supported by a sponsored project to M.S.G. from Valerion Therapeutics , NIH R01 NS070899 to M.S.G., P01 NS097197 to M.S.G., Epilepsy Foundation New Therapy Commercialization Grant to M.S.G., and F31 NS093892 to M.K.B. Funding for the University of Kentucky Alzheimer’s Disease Center ( P30 AGO28383 ) and the Biospecimen Procurement & Translational Pathology Shared Resource Facility of the UK Markey Cancer Center ( P30 CA177558 ) also contributed to this work.

Funding Information:
We thank Drs. Craig Vander Kooi and Jeffrey Rush of the University of Kentucky (UK) Department of Molecular and Cellular Biochemistry; Deb Ramsdell; and Drs. Beth Goad, Rob Schaffer, and Hal Landy of Valerion Therapeutics for valuable feedback and discussions. We also thank Drs. Berge Minassian and Felix Nitschke for fruitful discussions and recommendations. We appreciate the technical support of Dr. Carole Moncman, Azin Akbari, Nico Briot, the UK Electron Microscopy Core, Dr. Thomas Wilkop and the UK Light Microscopy Core, Dana Napier, and Karrie Jones. We also thank the UK Sanders-Brown Center on Aging and Adam Bachstetter for assistance with slide scanning and Biswa Choudhury and Sulabha Argade for their assistance with HPAEC-PAD experiments (GlycoAnalytics, University of California, San Diego, CA). This work is supported by a sponsored project to M.S.G. from Valerion Therapeutics, NIH R01 NS070899 to M.S.G. P01 NS097197 to M.S.G. Epilepsy Foundation New Therapy Commercialization Grant to M.S.G. and F31 NS093892 to M.K.B. Funding for the University of Kentucky Alzheimer's Disease Center (P30 AGO28383) and the Biospecimen Procurement & Translational Pathology Shared Resource Facility of the UK Markey Cancer Center (P30 CA177558) also contributed to this work. M.K.B. T.R.M. D.D.A. R.C.S. and M.S.G. conceived of the project and designed experiments. M.K.B. A.U. and G.L.A. performed experiments and analyzed data. D.M.S. A.D.-R. and P.J.R. made stable cell lines, performed VAL-0417 uptake studies, analyzed data, and provided Epm2b?/? tissues. J.J.M. performed i.m. injections. J.A.B. and A.U. performed i.v. injections. B.L.H. and J.R.P. designed experiments and analyzed data. J.Z. oversaw i.c.v. cannula implantations, injections, and euthanasia. R.C.S. and L.E.A.Y. performed metabolite extractions, mass spectrometry, and metabolomics data analysis. G.L.A. designed and optimized the ELISA. Z.R.S. and G.L.A. performed ELISA and amylase assay experiments. N.M.A. Z.Z. and G.L.A. performed image acquisition and analysis. M.K.B. R.C.S. and M.S.G. wrote the paper. D.D.A. is Chief Scientific Officer of and has an equity interest in Valerion Therapeutics. B.L.H. and T.R.M. are consultants of Valerion Therapeutics. M.S.G. received a sponsored project award from Valerion Therapeutics in accordance with University of Kentucky policies. The other authors declare that they have no competing interests. Valerion Therapeutics has filed one or more patent applications, including WO2018049237A1, of which D.D.A. is an inventor, related to AEF and its use.

Publisher Copyright:
© 2019 Elsevier Inc.

Keywords

  • Lafora bodies
  • Lafora disease
  • amylase
  • antibody-based drug
  • antibody-enzyme fusion
  • enzyme therapy
  • epilepsy
  • glycogen
  • glycogen storage disease
  • metabolomics

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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