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 earned my Bachelor's degree in Biochemistry and Master's degree in Translational Medicine from Universitat de Barcelona. During my internships, I joined dr. Hernández-Gea’s lab (Hepatic Hemodynamics and Portal Hypertension, IDIBAPS) for almost two years, where I conducted translational research on liver fibrosis, aiming to develop therapies to prevent fibrosis progression. Motivated by my interest in molecular therapies, I moved to the Netherlands to join Rob Collin and Alex Garanto’s group (Human Genetics Department, Radboudumc) as a PhD student within the StarT network. In here, I worked on the development of novel antisense oligonucleotide-based splice modulation therapies for deep-intronic ABCA4 mutations in Stargardt Disease. Being part of this PhD program provided a valuable opportunity to enhance various skills and meet experts in the field of inherited retinal diseases and RNA therapies, experiences that I believe positively influence my future career. I am set to defend my PhD thesis on May 16, 2024, at the Aula of Radboud University. Currently, I am working as a postdoctoral researcher to further investigate the potential of RNA therapeutics for Fuchs’ endothelial corneal dystrophy under the supervision of prof. dr. Rob Collin, and in collaboration with dr. Mor M. Dickman and dr. Vanessa LaPointe in Maastricht UMC. |
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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 optimize the efficacy of the AONs in a relevant cell model. These data will shed light on the pre-clinical efficacy of AON-based splice correction therapy for ABCA4-associated IRD, and allow to identify new targets for initiating clinical studies in humans.
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 optimize the efficacy of the AONs in a relevant cell model. These data will shed light on the pre-clinical efficacy of AON-based splice correction therapy for ABCA4-associated IRD, and allow to identify new targets for initiating clinical studies in humans.
