Antisense Oligonucleotide-Based Rescue of Aberrant Splicing Defects Caused by 15 Pathogenic Variants in <i>ABCA4</i>

• Main Authors: Tomasz Z. Tomkiewicz, Nuria Suárez-Herrera, Frans P. M. Cremers, Rob W. J. Collin, Alejandro Garanto
• Format: Article
• Language: English
• Published: MDPI AG 2021-04-01
• Series: International Journal of Molecular Sciences
• Subjects: antisense oligonucleotide; <i>ABCA4</i>; Stargardt disease; inherited retinal diseases; splicing modulation; RNA therapy
• Online Access: https://www.mdpi.com/1422-0067/22/9/4621
• ISSN: 1661-6596; 1422-0067

The discovery of novel intronic variants in the <i>ABCA4</i> locus has contributed significantly to solving the missing heritability in Stargardt disease (STGD1). The increasing number of variants affecting pre-mRNA splicing makes <i>ABCA4</i> a suitable candidate for antisense oligonucleotide (AON)-based splicing modulation therapies. In this study, AON-based splicing modulation was assessed for 15 recently described intronic variants (three near-exon and 12 deep-intronic variants). In total, 26 AONs were designed and tested in vitro using a midigene-based splice system. Overall, partial or complete splicing correction was observed for two variants causing exon elongation and all variants causing pseudoexon inclusion. Together, our results confirm the high potential of AONs for the development of future RNA therapies to correct splicing defects causing STGD1.