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

摘要

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 -N-benzy-2-acetamido-3-methoxypropionamide (( )-Lacosamide) in a mouse model of CLN6-Batten disease. Promisingly, mouse neuronal cultures as well as patient fibroblasts treated with varying concentrations of ( )-Lacosamide showed positive restoration of lysosomal associated deficits. However, while acute treatment enhanced glial activation in 3-month-old mutant mice, chronic treatment over several months did not improve behavioral or long-term survival outcomes. Therefore, modulation of CRMP2 activity via ( )-Lacosamide alone is unlikely to be a viable therapeutic target for CLN6-Batten disease.