Effect of intracerebroventricular administration of alglucosidase alfa in two mouse models of Lafora disease: Relevance for clinical practice

• Published in: Epilepsy research Vol. 200; p. 107317
• Main Authors: Zafra-Puerta, Luis, Colpaert, Matthieu, Iglesias-Cabeza, Nerea, Burgos, Daniel F., Sánchez-Martín, Gema, Gentry, Matthew S., Sánchez, Marina P., Serratosa, Jose M.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.02.2024
• Subjects: Alglucosidase alfa; alpha-Glucosidases; Animals; Glycogen - metabolism; Glycogen storage disease; Intracerebroventricular treatment; Lafora body; Lafora disease; Lafora Disease - drug therapy; Lafora Disease - genetics; Mice; Mice, Knockout; Protein Tyrosine Phosphatases, Non-Receptor - genetics; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Lafora body; Glycogen storage disease; Alglucosidase alfa; Intracerebroventricular treatment; Lafora disease
• ISSN: 0920-1211; 1872-6844
• DOI: 10.1016/j.eplepsyres.2024.107317

Lafora disease is a rare and fatal form of progressive myoclonic epilepsy with onset during early adolescence. The disease is caused by mutations in EPM2A, encoding laforin, or EPM2B, encoding malin. Both proteins have functions that affect glycogen metabolism, including glycogen dephosphorylation by laforin and ubiquitination of enzymes involved in glycogen metabolism by malin. Lack of function of laforin or malin results in the accumulation of polyglucosan that forms Lafora bodies in the central nervous system and other tissues. Enzyme replacement therapy through intravenous administration of alglucosidase alfa (Myozyme®) has shown beneficial effects removing polyglucosan aggregates in Pompe disease. We evaluated the effectiveness of intracerebroventricular administration of alglucosidase alfa in the Epm2a-/- knock-out and Epm2aR240X knock-in mouse models of Lafora disease. Seven days after a single intracerebroventricular injection of alglucosidase alfa in 12-month-old Epm2a-/- and Epm2aR240X mice, the number of Lafora bodies was not reduced. Additionally, a prolonged infusion of alglucosidase alfa for 2 or 4 weeks in 6- and 9-month-old Epm2a-/- mice did not result in a reduction in the number of LBs or the amount of glycogen in the brain. These findings hold particular significance in guiding a rational approach to the utilization of novel therapies in Lafora disease. •Single ICV injection or infusion of alglucosidase alfa do not remove Lafora bodies in the mouse brain.•Single ICV injection or infusion of alglucosidase alfa do not revert neurological alterations in the mouse model of Lafora disease.•There is no evidence from animal studies to support the use of alglucosidase alfa for the treatment of Lafora disease.