Wan Ledong, Kral Alexander J, Voss Dillon, Krainer Adrian R
bioRxiv. 2023 Apr 3:2023.03.31.535161. doi: 10.1101/2023.03.31.535161.
Aberrant alternative splicing is emerging as a cancer hallmark and a potential therapeutic target. It is the result of dysregulated splicing factors or genetic alterations in splicing-regulatory -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 (PDOs) 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) transfection method to systematically evaluate and screen individual splicing events as therapeutic targets in pancreatic ductal adenocarcinoma (PDAC) organoids. This optimized delivery method allows fast and efficient screening of ASOs that reverse oncogenic alternative splicing. In combination with advancements in chemical modifications and ASO-delivery strategies, this method has the potential to accelerate the discovery of anti-tumor ASO drugs that target pathological alternative splicing.
异常可变剪接正在成为一种癌症标志和潜在的治疗靶点。它是剪接因子失调或剪接调控元件发生基因改变的结果。针对与癌细胞依赖性相关的单个异常剪接事件是一种潜在的治疗策略，但需要解决几个技术限制。患者来源的类器官（PDO）是一个很有前景的平台，可概括疾病状态的关键方面并促进精准医学的药物开发。在此，我们报告了一种高效的反义寡核苷酸（ASO）转染方法，用于系统评估和筛选作为胰腺导管腺癌（PDAC）类器官治疗靶点的单个剪接事件。这种优化的递送方法能够快速高效地筛选出可逆转致癌性可变剪接的ASO。结合化学修饰和ASO递送策略的进展，该方法有潜力加速发现针对病理性可变剪接的抗肿瘤ASO药物。
