Antisense oligonucleotides (AONs) are synthetic molecules that can bind to pre-mRNA and as a consequence interfere with pre-mRNA splicing. Therapeutically, AONs can be employed in various ways to correct splicing defects resulting from genetic mutations, or modulate gene expression via RNA silencing.
Our scientific approach for treatment of Stargardt disease
Radboudumc scientists have developed AONs for the treatment of Stargardt disease, by correcting various mutant ABCA4 transcripts. The versatility of AONs allows these molecules to be used in a number of different ways. The most straightforward use of AONs -which is also applied in Astherna’s first AON therapy for Stargardt disease- is to prevent the recognition of pseudoexons. Astherna builds on the inventions and knowledge gathered during years of research by the Radboudumc, to now bring novel therapeutics to patients.
How does Astherna’s AON therapy work?
Many deep-intronic mutations in ABCA4 lead to the activation of cryptic splice acceptor sites, cryptic splice donor sites or exonic splice enhancers, all resulting in the insertion of a pseudoexon that in the majority of cases leads to premature termination of protein synthesis. AONs can be designed to block pseudoexon recognition, and thereby restore proper RNA and protein synthesis. In addition to relatively straightforward single-gene IRD’s, AONs can further be applied to modulate gene expression in multifactorial retinal diseases.
The potential of AON therapy for Stargardt disease
Targeting splicing defects in ABCA4 with AONs provides an excellent opportunity to specifically rescue aberrant RNA processing, with the means to treat a significant part of the collective patient pool and prevent further visual impairment in thousands of patients with STGD1 worldwide. For the initial development, we often use patient-derived body material (blood or a skin biopsy) combined with cutting-edge technology to generate cellular models that mimic certain disease characteristics.