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Stargardt disease is the most common inherited macular dystrophy, with a global prevalence of around 1:10.000 individuals, leading to progressive central vision loss and visual impairment. In a newly published research article Zelia Corradi and colleagues, in the Blindness Genetics team headed by Frans Cremers and in collaboration with the Blindness Genetics Therapy (Rob Collin and Alejandro Garanto), investigate the potential of small RNA molecules to target the genetic causes of the disease. The full article describing this research project was published on Nucleic Acid Therapeutics on 27 May 2024.
Loss of vision in persons with Stargardt disease is the result of the accumulation of toxic products in the retina, which causes the death of its light sensitive cells, the photoreceptors. The ABCA4 gene encodes the transporter protein ABCA4, which has a key role in the elimination of toxic products in photoreceptors, and pathogenic variants in this gene underlie Stargardt disease.
The Blindness Genetics group of the Human Genetics department of the Radboudumc has a long-standing interest in studying a specific category of ABCA4 variants, located in the non-coding regions of the gene (introns). These deep-intronic variants can disrupt the biological process through which the introns are cut out and the coding parts (exons) are stitched together to form the final RNA sequence encoding the ABCA4 protein. In ABCA4, deep-intronic variants are a well-known cause of Stargardt disease, which makes them an interesting therapeutic target.
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Antisense oligonucleotides, frequently referred to as AONs, are single stranded synthetic RNA molecules that can be designed to bind to targets in a RNA and regulate the splicing process. AONs are a great asset in the fast expanding field of personalized medicine, which aims at determining the best treatment for a single patient in a personalized manner. This novel way of conceiving therapeutic approaches is especially promising for patients that carry extremely rare intronic variants in ABCA4. In such cases, AONs can be used to prevent incorrect splicing from occurring and increase the levels of functional protein.
In this recently published work, the researches show the effectiveness of AON therapeutics in rescuing particularly complex splicing defects in ABCA4, using an in vitro system that allows to model the defects in immortalized human kidney cells. Additionally, they show that single AONs effectively work to target hotspot regions where multiple pathogenic variants are present, allowing to broaden the therapeutic potential of AONs personalized therapies. In the future, further investigation on the implementation of AONs in more complex research model will lead the way towards translating these promising results in a clinical setting.
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Read the publication here: https://doi.org/10.1089/nat.2024.0008
Corradi Z, Hitti-Malin RJ, de Rooij LA, Garanto A, Collin RWJ, Cremers FPM. Antisense Oligonucleotide-Based Rescue of Complex Intronic Splicing Defects in ABCA4. Nucleic Acid Ther. 2024 May 27. doi: 10.1089/nat.2024.0008. Epub ahead of print. PMID: 38800942.
