Screening Splice-Switching Antisense Oligonucleotides in Pancreas-Cancer Organoids

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

DOI: 10.1089/nat.2023.0070


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: 17 May 2024 12:38
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