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

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 journal › Article › peer-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 language	English
Pages (from-to)	689-705.e6
Journal	Cell Metabolism
Volume	30
Issue number	4
DOIs	https://doi.org/10.1016/j.cmet.2019.07.002
State	Published - 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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10.1016/j.cmet.2019.07.002

Cite this

Brewer, M. K., Uittenbogaard, A., Austin, G. L., Segvich, D. M., DePaoli-Roach, A., Roach, P. J., McCarthy, J. J., Simmons, Z. R., Brandon, J. A., Zhou, Z., Zeller, J., Young, L. E. A., Sun, R. C., Pauly, J. R., Aziz, N. M., Hodges, B. L., McKnight, T. R., Armstrong, D. D., & Gentry, M. S. (2019). Targeting Pathogenic Lafora Bodies in Lafora Disease Using an Antibody-Enzyme Fusion. Cell Metabolism, 30(4), 689-705.e6. https://doi.org/10.1016/j.cmet.2019.07.002

@article{5688e197d07349ab900b9bbc012bd513,

title = "Targeting Pathogenic Lafora Bodies in Lafora Disease Using an Antibody-Enzyme Fusion",

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.",

keywords = "Lafora bodies, Lafora disease, amylase, antibody-based drug, antibody-enzyme fusion, enzyme therapy, epilepsy, glycogen, glycogen storage disease, metabolomics",

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

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{\textquoteright}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: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

month = oct,

day = "1",

doi = "10.1016/j.cmet.2019.07.002",

language = "English",

volume = "30",

pages = "689--705.e6",

number = "4",

}

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 & Gentry, MS 2019, 'Targeting Pathogenic Lafora Bodies in Lafora Disease Using an Antibody-Enzyme Fusion', Cell Metabolism, vol. 30, no. 4, pp. 689-705.e6. https://doi.org/10.1016/j.cmet.2019.07.002

TY - JOUR

T1 - Targeting Pathogenic Lafora Bodies in Lafora Disease Using an Antibody-Enzyme Fusion

AU - Brewer, M. Kathryn

AU - Uittenbogaard, Annette

AU - Austin, Grant L.

AU - Segvich, Dyann M.

AU - DePaoli-Roach, Anna

AU - Roach, Peter J.

AU - McCarthy, John J.

AU - Simmons, Zoe R.

AU - Brandon, Jason A.

AU - Zhou, Zhengqiu

AU - Zeller, Jill

AU - Young, Lyndsay E.A.

AU - Sun, Ramon C.

AU - Pauly, James R.

AU - Aziz, Nadine M.

AU - Hodges, Bradley L.

AU - McKnight, Tracy R.

AU - Armstrong, Dustin D.

AU - Gentry, Matthew S.

N1 - 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.

PY - 2019/10/1

Y1 - 2019/10/1

N2 - 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.

AB - 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.

KW - Lafora bodies

KW - Lafora disease

KW - amylase

KW - antibody-based drug

KW - antibody-enzyme fusion

KW - enzyme therapy

KW - epilepsy

KW - glycogen

KW - glycogen storage disease

KW - metabolomics

UR - http://www.scopus.com/inward/record.url?scp=85070676736&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85070676736&partnerID=8YFLogxK

U2 - 10.1016/j.cmet.2019.07.002

DO - 10.1016/j.cmet.2019.07.002

M3 - Article

C2 - 31353261

AN - SCOPUS:85070676736

SN - 1550-4131

VL - 30

SP - 689-705.e6

JO - Cell Metabolism

JF - Cell Metabolism

IS - 4

ER -

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

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Bibliographical note

Keywords

ASJC Scopus subject areas

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