AAV-mediated exon skipping therapy for Usher syndrome, type 2A

Area of Science:

• Genetics
• Ophthalmology
• Otolaryngology

Background:

• Usher syndrome causes vision, hearing, and balance loss, with USH2A mutations being the most common worldwide.
• The frequent USH2A c.2299delG mutation leads to Usher syndrome, currently managed with investigational antisense oligonucleotides (ASOs) requiring repeated injections.
• Current ASO treatments for USH2A may necessitate repeated administrations for sustained efficacy.

Purpose of the Study:

• To develop a vectorized ASO exon skipping strategy for USH2A.
• To overcome the limitation of repeated injections for long-term ASO efficacy.
• To create a potential one-time local treatment for USH2A patients.

Main Methods:

• Screening of USH2A exon 13 skippers and adeno-associated virus (AAV) capsids.
• Development of optimized vectorized ASO constructs.
• Evaluation in human stem cell-derived inner ear and retinal organoids with the USH2A c.2299delG mutation.

Main Results:

• Enhanced skipping of the pathogenic USH2A exon was achieved.
• Optimized vectors and skippers demonstrated efficacy in organoid models.
• The vectorized ASO strategy showed potential for Usher syndrome treatment.

Conclusions:

• A vectorized ASO exon skipping strategy offers a promising alternative for USH2A treatment.
• This approach may enable a single local injection to prevent vision and hearing loss progression.
• Further development could lead to a novel therapeutic option for Usher syndrome patients.