Wan, Ledong, Kral, Alexander J, Voss, Dillon, Schäfer, Balázs, Sudheendran, Kavitha, Danielsen, Mathias, Caruthers, Marvin H, Krainer, Adrian R (May 2024) Screening Splice-Switching Antisense Oligonucleotides in Pancreas-Cancer Organoids. Nucleic Acid Therapeutics. ISSN 2159-3337
Abstract
Aberrant alternative splicing is emerging as a cancer hallmark and a potential therapeutic target. It is the result of dysregulated or mutated splicing factors, or genetic alterations in splicing-regulatory cis-elements. Targeting individual altered splicing events associated with cancer-cell dependencies is a potential therapeutic strategy, but several technical limitations need to be addressed. Patient-derived organoids are a promising platform to recapitulate key aspects of disease states, and to facilitate drug development for precision medicine. Here, we report an efficient antisense-oligonucleotide (ASO) lipofection method to systematically evaluate and screen individual splicing events as therapeutic targets in pancreatic ductal adenocarcinoma organoids. This optimized delivery method allows fast and efficient screening of ASOs, e.g., those that reverse oncogenic alternative splicing. In combination with advances in chemical modifications of oligonucleotides and ASO-delivery strategies, this method has the potential to accelerate the discovery of antitumor ASO drugs that target pathological alternative splicing.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders Investigative techniques and equipment Investigative techniques and equipment > cell culture > cancer organoids Investigative techniques and equipment > cell culture diseases & disorders > cancer > cancer types > pancreatic cancer diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL Cancer Center Program > Gene Regulation and Inheritance Program CSHL labs > Krainer lab CSHL Cancer Center Program |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 8 May 2024 |
| Date Deposited: | 17 May 2024 12:38 |
| Last Modified: | 01 Oct 2024 17:55 |
| PMCID: | PMC11387002 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/41549 |
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