Characterizing Stargardt Disease Mutations for Splice Intervention Therapeutics

Project Aim

The aim of this project was to find a treatment for Stargardt disease, an inherited genetic eye condition caused by mutations in the ABCA4 gene. It studied the specific genetic changes in the ABCA4 gene that lead to the disease to develop a type of treatment called splice-switching antisense oligonucleotides (SS-AONs).

Project Summary

In this project, the team screened 30 patients with Stargardt disease and identified several ABCA4 gene variants that disrupted how the gene’s message is processed, confirming that faulty splicing plays a significant role in disease development. They then successfully reprogrammed skin cells from selected patients into stem cells, which serve as a powerful platform for generating retinal cells and studying the effects of these genetic changes more closely.

Based on computational predictions, the team designed targeted SS-AONs to correct the faulty gene message. When tested in patient-derived cells, these molecules effectively restored the full-length, correct version of the gene message, demonstrating the potential of this approach to correct the underlying genetic defect.

Research Impact and Significance

Together, the team’s findings validate splice correction as a viable therapeutic strategy for Stargardt disease and lay essential groundwork for the development of personalised, gene-based treatments. This research not only advances our understanding of how specific gene mutations contribute to inherited vision loss but also creates a scalable model for testing future therapies—bringing us a step closer to the first targeted treatment for Stargardt disease and offering broader insights into treating other inherited retinal disorders.

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