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The research led by the groups of Alex Garanto (Radboudumc, Dept. Pediatrics) and Enrico Mastrobattista (Utrecht University, Dept. Pharmaceutics) in collaboration with Rob Collin (Radboudumc, Dept. Human Genetics) describes a novel, and efficient method to target multiple deep-intronic pathogenic variants in the ABCA4 gene. Using a lipopeptide-mediated delivery system combined with CRISPR-Cas9 technology, harmful intronic variants in the ABCA4 gene were removed, offering a novel therapeutic strategy for Stargardt disease (STGD1).
STGD1 is a leading cause of inherited macular degeneration, caused by pathogenic variants in the ABCA4 gene. Approximately 10-12% of these mutations are deep-intronic variants that disrupt normal gene function by altering splicing. Current treatments, such as antisense oligonucleotides, are often mutation-specific, limiting their use to a small group of patients. This project aimed to develop a mutation-independent approach by using CRISPR-Cas9 gene editing combined with a lipopeptide delivery system (C18:1-LAH5).
This combination of delivery method and genome editing technology effectively removed intronic regions containing the variants of interest in cells derived from control and STGD1 individuals. The partial removal of the introns studied in this work did not affect splicing nor gene expression, highlighting the therapeutic potential of this strategy. The next steps involve further testing in more complex models, such as retinal organoids, with a focus on optimizing the molecule and delivery method for potential clinical use.
About the publication
Vázquez-Domínguez, I., Öktem, M., Winkelaar, F.A., Nguyen, T.H., et al. (2024). Lipopeptide-mediated Cas9 RNP delivery: A promising broad therapeutic strategy for safely removing deep-intronic variants in ABCA4. Molecular Therapy: Nucleic Acids.
