Modulation of CRMP2 via (S)-Lacosamide shows therapeutic promise but is ultimately ineffective in a mouse model of CLN6-Batten disease

Katherine A White; Jacob T Cain; Helen Magee; Seul Ki Yeon; Ki Duk Park; Rajesh Khanna; Jill M Weimer

doi:10.1042/NS20190001

Modulation of CRMP2 via (S)-Lacosamide shows therapeutic promise but is ultimately ineffective in a mouse model of CLN6-Batten disease

Neuronal Signal. 2019 Jun;3(2):NS20190001. doi: 10.1042/NS20190001. Epub 2019 Apr 8.

Authors

Katherine A White¹, Jacob T Cain¹, Helen Magee^{1

2}, Seul Ki Yeon³, Ki Duk Park³, Rajesh Khanna⁴, Jill M Weimer^{1

5}

Affiliations

¹ Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, U.S.A.
² Basic Biomedical Sciences, University of South Dakota Sanford School of Medicine, Vermillion, SD, U.S.A.
³ Convergence Research Center for Dementia, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea.
⁴ Department of Pharmacology, University of Arizona, Tucson, AZ, U.S.A.
⁵ Department of Pediatrics, University of South Dakota, Sioux Falls, SD, U.S.A.

Abstract

CLN6-Batten disease is a rare neurodegenerative disorder with no cure, characterized by accumulation of lipofuscin in the lysosome, glial activation, and neuronal death. Here we test the therapeutic efficacy of modulating collapsin response mediator protein 2 (CRMP2) activity via S-N-benzy-2-acetamido-3-methoxypropionamide ((S)-Lacosamide) in a mouse model of CLN6-Batten disease. Promisingly, mouse neuronal cultures as well as Cln6 patient fibroblasts treated with varying concentrations of (S)-Lacosamide showed positive restoration of lysosomal associated deficits. However, while acute in vivo treatment enhanced glial activation in 3-month-old Cln6 mutant mice, chronic treatment over several months did not improve behavioral or long-term survival outcomes. Therefore, modulation of CRMP2 activity via (S)-Lacosamide alone is unlikely to be a viable therapeutic target for CLN6-Batten disease.

Keywords: Batten disease; CRMP2; Lacosamide; neuronal ceroid lipofuscinosis; repurposed pharmaceuticals.

Abstract

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