Malin restoration as proof of concept for gene therapy for Lafora disease
Author
Varea, Olga
Guinovart, Joan
Duran Castells, Jordi
Other authors
Universitat Ramon Llull. IQS
Publication date
2022ISSN
2632-1297
Abstract
Lafora disease is a fatal neurodegenerative childhood dementia caused by loss-of-function mutations in either the laforin or malin gene. The hallmark of the disease is the accumulation of abnormal glycogen aggregates known as Lafora bodies (LBs) in the brain and other tissues. These aggregates are responsible for the pathological features of the disease. As a monogenic disorder, Lafora disease is a good candidate for gene therapy-based approaches. However, most patients are diagnosed after the appearance of the first symptoms and thus when LBs are already present in the brain. In this context, it was not clear whether the restoration of a normal copy of the defective gene (either laforin or malin) would prove effective. Here we evaluated the effect of restoring malin in a malin-deficient mouse model of Lafora disease as a proof of concept for gene replacement therapy. To this end, we generated a malin-deficient mouse in which malin expression can be induced at a certain time. Our results reveal that malin restoration at an advanced stage of the disease arrests the accumulation of LBs in brain and muscle, induces the degradation of laforin and glycogen synthase bound to the aggregates, and ameliorates neuroinflammation. These results identify malin restoration as the first therapeutic strategy to show effectiveness when applied at advanced stages of Lafora disease.
Document Type
Article
Document version
Published version
Language
English
Subject (CDU)
616.8 - Neurology. Neuropathology. Nervous system
Keywords
Glycogen
Lafora disease
Neurodegeneration
Neuroinflammation
Gene therapy
Glicogen
Teràpia genètica
Sistema nerviós--Degeneració
Pages
p.14
Publisher
Oxford University Press
Is part of
Brain Communications 2022, 4(4), fcac168
Grant agreement number
info:eu-repo/grantAgreement/MEIC/PN I+D/BFU2017-84345-P
info:eu-repo/grantAgreement/MCI/PN I+D/PID2020-118699GB-I00
info:eu-repo/grantAgreement/NIH/NINDS/P01NS097197
This item appears in the following Collection(s)
Rights
© L'autor/a
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/