Efficient brain molecular therapy for Duchenne muscular dystrophy
Partial restoration of brain dystrophin by exon skipping improves behavioral deficits in mdx mice, a model of Duchenne muscular dystrophy Duchenne muscular dystrophy is associated with various degrees of cognitive and behavioral disorders. Teams from UVSQ (A. Goyenvalle) and NeuroPSI (C. Vaillend) have been studying for several years the potential reversibility of these disorders by attempting to re-express the dystrophin Dp427 in the adult brain of mdx mice, a mouse model of Duchenne muscular dystrophy. To do this, they are using antisense oligonucleotides targeting the mutated exon 23 of the dystrophin mRNA in order to exclude the mutation, and to restore the reading frame and expression of a functional dystrophin.
In a study recently published in Annals of Neurology, these research teams demonstrated that intracerebroventricular injection of these antisense oligonucleotides allows a restoration of dystrophin expression (from 10 to 30% of WT levels) in different brain regions (hippocampus, cortex, cerebellum). This partial restoration significantly reduced unconditioned fear in mdx mice, a major phenotype reflecting amygdala-dependent stress hyperreactivity. Furthermore, this treatment improved performance of treated mice in a task involving hippocampal-dependent recognition memory, but had only minor effects on conditioned fear responses. These results suggest for the first time that postnatal reexpression of dystrophin in the brain may alleviate some of the cognitive deficits associated with DMD.
Partial Restoration of Brain Dystrophin and Behavioral Deficits by Exon Skipping in the Muscular Dystrophy X-Linked (mdx) Mouse. Faouzi Zarrouki, Karima Relizani, Flavien Bizot, Thomas Tensorer, Luis Garcia, Cyrille VaillendD, Aurélie Goyenvalle.