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Updated: Jul 2, 2026
Assessing Functional Performance in the Mdx Mouse Model
Published on: March 27, 2014
Ineffective behavioral rescue despite partial brain Dp427 restoration by AAV9-U7-mediated exon 51 skipping in mdx52
Ophélie Vacca1, Amel Saoudi1, Mathilde Doisy1
1Université Paris-Saclay, UVSQ, Inserm, END-ICAP, 78000 Versailles, France.
Abstract:
The mdx52 mouse model exhibits a common mutation profile associated with brain involvement in Duchenne muscular dystrophy (DMD), characterized by heightened anxiety, fearfulness, and impaired associative fear learning. Deletion of exon 52 disrupts the expression of two dystrophins found in the brain (Dp427 and Dp140) and is eligible for therapeutic exon-skipping strategies. We previously demonstrated that a single intracerebroventricular administration of an antisense oligonucleotide (ASO) targeting exon 51 of the Dmd gene could restore 5%-15% of Dp427 expression. This treatment reduced anxiety and unconditioned fear in mdx52 mice, improved fear conditioning acquisition, and partially improved fear memory tested 24 h later. To improve the restoration of Dp427 and induce a long-lasting therapeutic effect, we employed a vectorized approach using an adeno-associated virus (AAV)-U7 small nuclear RNA vector to deliver antisense sequences to the brains of mdx52 mice. We evaluated two AAV serotypes known for their brain transduction efficiency (AAV9 and RH10) and two delivery routes, intracisterna magna and intracerebroventricular (ICV) injections, to maximize brain targeting. Based on GFP expression data, we selected the AAV9 capsid and a bilateral ICV delivery route. Using this approach, we demonstrated that ICV administration of AAV9-U7-Ex51M induced exon 51 skipping and restored Dp427 expression in the brains of adult mdx52 mice, though with significant variability among individuals. While a few mice showed high Dp427 expression levels, the average restoration was limited to approximately 6%-12%. In conclusion, inducing exon skipping in the brains of adult mdx52 mice using the vectorized AAV9-U7 approach was less effective than synthetic ASO treatment and did not improve the emotional behavior of mdx52 mice.
Insights
Vectorized gene therapy using adeno-associated virus (AAV) did not improve brain function in Duchenne muscular dystrophy (DMD) mice. This approach was less effective than antisense oligonucleotide (ASO) treatment for restoring dystrophin expression and behavior.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Duchenne muscular dystrophy (DMD) involves brain complications, including anxiety and impaired fear learning, in the mdx52 mouse model.
- Exon 52 deletion in mdx52 mice affects brain dystrophin expression (Dp427, Dp140), making it a target for exon-skipping therapies.
- Previous studies showed limited success with antisense oligonucleotide (ASO) treatment for restoring Dp427 and improving behavior.
Purpose of the Study:
- To evaluate a vectorized gene therapy approach using adeno-associated virus (AAV) for restoring Dp427 expression in the mdx52 mouse brain.
- To compare the efficacy of AAV-mediated exon skipping with previous ASO treatments.
- To assess the impact of AAV-mediated Dp427 restoration on anxiety and fear learning behaviors in mdx52 mice.
Main Methods:
- Utilized an adeno-associated virus (AAV)-U7 small nuclear RNA vector to deliver antisense sequences targeting exon 51 of the Dmd gene.
- Administered the vector via intracerebroventricular (ICV) injections in adult mdx52 mice, testing AAV9 and RH10 serotypes.
- Assessed exon 51 skipping, Dp427 expression levels, and behavioral outcomes (anxiety, fear conditioning).
Main Results:
- AAV9 vector delivered via bilateral ICV injections induced exon 51 skipping and Dp427 restoration, but with significant individual variability.
- Average Dp427 expression restoration was limited to 6%-12%, lower than previously achieved with ASO treatment.
- The AAV-mediated approach did not improve anxiety or fear-related behaviors in the mdx52 mice.
Conclusions:
- Vectorized AAV-U7 gene therapy for exon skipping in the adult mdx52 mouse brain is less effective than synthetic ASO treatment.
- This vectorized approach failed to yield significant behavioral improvements in the studied emotional domains.
- Further optimization of gene delivery and therapeutic strategies is needed for treating brain-related symptoms in DMD.
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