Saoudi, Amel;
Barberat, Sacha;
le Coz, Olivier;
Vacca, Ophélie;
Doisy Caquant, Mathilde;
Tensorer, Thomas;
Sliwinski, Eric;
... Goyenvalle, Aurélie; + view all
(2023)
Partial restoration of brain dystrophin by tricyclo-DNA antisense oligonucleotides alleviates emotional deficits in mdx52 mice.
Molecular Therapy - Nucleic Acids
, 32
pp. 173-188.
10.1016/j.omtn.2023.03.009.
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Abstract
The mdx52 mouse model recapitulates a frequent mutation profile associated with brain involvement in Duchenne muscular dystrophy. Deletion of exon 52 impedes expression of two dystrophins (Dp427, Dp140) expressed in brain, and is eligible for therapeutic exon-skipping strategies. We previously showed that mdx52 mice display enhanced anxiety and fearfulness, and impaired associative fear learning. In this study, we examined the reversibility of these phenotypes using exon 51 skipping to restore exclusively Dp427 expression in the brain of mdx52 mice. We first show that a single intracerebroventricular administration of tricyclo-DNA antisense oligonucleotides targeting exon 51 restores 5%-15% of dystrophin protein expression in the hippocampus, cerebellum, and cortex, at stable levels between 7 and 11 week after injection. Anxiety and unconditioned fear were significantly reduced in treated mdx52 mice and acquisition of fear conditioning appeared fully rescued, while fear memory tested 24 h later was only partially improved. Additional restoration of Dp427 in skeletal and cardiac muscles by systemic treatment did not further improve the unconditioned fear response, confirming the central origin of this phenotype. These findings indicate that some emotional and cognitive deficits associated with dystrophin deficiency may be reversible or at least improved by partial postnatal dystrophin rescue.
Type: | Article |
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Title: | Partial restoration of brain dystrophin by tricyclo-DNA antisense oligonucleotides alleviates emotional deficits in mdx52 mice |
Location: | United States |
Open access status: | An open access version is available from UCL Discovery |
DOI: | 10.1016/j.omtn.2023.03.009 |
Publisher version: | https://doi.org/10.1016/j.omtn.2023.03.009 |
Language: | English |
Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
Keywords: | CNS delivery, Duchenne muscular dystrophy, MT: Oligonucleotides: Therapies and Applications, antisense oligonucleotides, brain comorbidities, exon-skipping |
UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept |
URI: | https://discovery.ucl.ac.uk/id/eprint/10169329 |
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