Purpose of the STSM:  Duchenne muscular dystrophy (DMD) is a genetic disorder characterised by progressive muscle
degeneration, cognitive and neurodevelopmental issues. It is caused by mutations to the DMD gene, leading to absences/deficiencies in dystrophin isoforms. Depending on where the mutations occur in the gene, the severity and nature of the neurological symptoms can vary due to the absence of particular isoforms usually expressed in the brain (Dp427, Dp140, Dp71).
Some of the most promising treatments for DMD in recent years use antisense oligonucleotides (ASOs) in exon skipping strategies to skip out-of-frame exons and restore the reading frame. Currently, the applicant’s group at Trinity College Dublin, is investigating ASO therapies to restore dystrophin isoforms in the brain and thereby alleviate the neurological and cognitive defects observed.

The mouse model of DMD, mdx52, represents a useful model for investigation of these isoforms and their role in the brain. Due to disruption of exon 52, this mouse model lacks Dp427 and Dp140 isoforms. Restoration of Dp427 can be achieved by skipping exon 51, which they have recently been investigating through administration locally in the brain. However, they hope to optimise ASO sequences to skip exon 53, to restore both Dp140 and Dp427. Before local administration, the sequences need to be assessed to confirm they will cause exon skipping. In this regard, Prof. Goyenvalle’s group, the host laboratory, routinely test ASO sequence in vitro in H2K-mdx52 primary myoblasts and in vivo through intramuscular injection of the tibialis anterior muscle. Thus, this STSM grant was sought to gain expertise in in vitro primary myoblasts transfection and culture and in vivo TA muscle administration.

Grantee name: Claire Fergus

STSM start and end date: 24/07/2022 to 31/07/2022

Title: Exon53 skipping in mdx52 mouse model of DMD – optimisation of oligonucleotide sequence and delivery
Host lab: Prof. Aurélie Goyenvalle, Université de Versailles Saint-Quentin-en-Yvelines (Versailles, France)