ESR9: Antisense oligonucleotide-based splice modulation for deep-intronic mutations in ABCA4

Partner
Radboud University Medical Center Nijmegen, The Netherlands (www.ru.nl/donders/research/theme-2-perception-action-control/research-groups-theme-2/genetic-therapy-inherited-retinal-disease/)
Supervisor
Dr. R. Collin

Nuria Suárez Herrera
I obtained my BSc in Biochemistry and MSc in Translational Medicine at Universitat de Barcelona. At that time, I did an internship for almost two years in Dr. Hernández-Gea’s lab (Hepatic Hemodynamics and Portal Hypertension, IDIBAPS), where I conducted translational research in liver fibrosis, aiming to develop therapies to prevent fibrosis progression. Afterwards, driven by my interest in bench-to-bedside research, I joined Dr. Collin’s group (Human Genetics Department, Radboudumc) as a PhD student in StarT Project, where I am currently working on the development of novel antisense oligonucleotide-based splice modulation therapies for deep-intronic ABCA4 mutations in Stargardt Disease.

Abstract
Antisense oligonucleotides (AONs) are molecules that are able to modulate pre-mRNA splicing of target genes, either by blocking or by recruiting factors that are essential for splicing. P1-UGent, P2-RUMC and others have identified several deep-intronic ABCA4 variants that result in the insertion of pseudexons into ABCA4 mRNA (e.g. c.4539+1100A>G; c.4539+1106C>T; c.4539+2001G>A and c.4539+2028C>T). In this project, ESR9 will employ AONs to redirect ABCA4 splicing in order to produce wild-type ABCA4 transcripts, employing patient-derived fibroblasts or minigene splicing assays. Following the identification of the most potent AON molecules for each mutation iPSC-derived PPCs from patients with the corresponding mutations will be generated. Subsequently, AONs will be administered to these PPCs, to further optimise the efficacy of the AONs in a relevant cell model. ESR9 will employ transcriptomics  to study potential off-target effects of AON administration. These data will shed light on the pre-clinical efficacy and safety of AON-based splice correction therapy for ABCA4-associated IRD, and allow to identify new targets for initiating clinical studies in humans.