About antisense oligonucleotides
Antisense oligonucleotides (ASOs) are synthetic molecules that can bind to pre-mRNA and as a consequence interfere with pre-mRNA splicing. Therapeutically, ASOs can be employed in various ways to correct splicing defects resulting from genetic mutations, to induce the in frame skipping mutated native exons, or modulate gene expression via RNA silencing.
Addressing inherited retinal diseases at their source
Vision loss affects far more than eyesight. It can change how people work, travel, connect with others and live their daily lives.At Astherna, we are developing new treatments for inherited retinal diseases with the aim of slowing or preventing vision loss. Building on years of research at Radboudumc, we focus on translating scientific advances into therapies that have the potential to make a real difference for patients.
Everything we do is guided by a simple ambition to help people preserve their sight and maintain their independence for longer.
How do Astherna’s ASO therapies 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. ASOs can be designed to block pseudoexon recognition, and thereby restore proper RNA and protein synthesis.
Loss-of-function mutations in the coding region of USH2A result in USH2A-associated retinitis pigmentosa, either under form of Usher syndrome type 2A or non-syndromic retinitis pigmentosa. These mutations result in the premature termination of protein translation or misfolding of the usherin protein. ASOs designed to block the incorporation of these mutated exons during pre-mRNA splicing, result in the translation of a slightly shortened usherin protein with enough residual function to maintain visual function and photoreceptor integrity. In addition to relatively straightforward single-gene IRDs, ASOs can further be applied to modulate gene expression in multifactorial retinal diseases.
The potential of ASO therapy for inherited retinal diseases
Targeting splicing defects in ABCA4 with ASOs provide 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 Stargardt disease 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. For USH2A-associated retinitis pigmentosa, targeted skipping of mutated exons has high therapeutic potential for patients having mutations in carefully selected exons. During pre-clinical development, we make use of the powerful combination of zebrafish models and patient-derived 3D organoid models to show therapeutic efficacy.