RNA 剪接调控彻底改变了挑战性疾病的治疗。神经内分泌癌，包括小细胞肺癌（SCLC）和神经内分泌前列腺癌（PCa），具有高度侵袭性，具有转移性神经内分泌表型，导致患者预后不佳。我们研究了基于酰胺桥核酸 (AmNA) 的剪接转换寡核苷酸 (SSO)，其靶向 RE1 沉默转录因子 (REST) 剪接作为一种新型疗法。我们设计了基于 AmNA 的 SSO 来改变 REST 拼接。通过将 SCLC 或 PCa 细胞皮下植入小鼠体内来产生肿瘤异种移植物。腹膜内施用 SSO 或盐水并监测肿瘤生长。 SSO给药后从小鼠身上采集血样，并使用生化分析仪测量血清丙氨酸转氨酶和天冬氨酸转氨酶水平以评估肝毒性。 在体外，REST_SSO 降低了癌细胞的活力。在肿瘤异种移植模型中，它表现出显着的抗肿瘤作用。它抑制 REST 控制的 RE1 携带基因并上调 miR-4516（一种 SCLC 生物标志物）。我们的研究结果表明，REST_SSO 通过恢复 REST 功能来抑制神经内分泌癌的肿瘤发生。这种新颖的治疗方法有望治疗 SCLC 和神经内分泌 PCa 等难治性神经内分泌癌。© 2024 作者。

RNA splicing regulation has revolutionized the treatment of challenging diseases. Neuroendocrine cancers, including small cell lung cancer (SCLC) and neuroendocrine prostate cancer (PCa), are highly aggressive, with metastatic neuroendocrine phenotypes, leading to poor patient outcomes. We investigated amido-bridged nucleic acid (AmNA)-based splice-switching oligonucleotides (SSOs) targeting RE1-silencing transcription factor (REST) splicing as a novel therapy. We designed AmNA-based SSOs to alter REST splicing. Tumor xenografts were generated by subcutaneously implanting SCLC or PCa cells into mice. SSOs or saline were intraperitoneally administered and tumor growth was monitored. Blood samples were collected from mice after SSO administration, and serum alanine aminotransferase and aspartate aminotransferase levels were measured to assess hepatotoxicity using a biochemical analyser. In vitro, REST_SSO reduced cancer cell viability. In a tumor xenograft model, it exhibited significant antitumor effects. It repressed REST-controlled RE1-harboring genes and upregulated miR-4516, an SCLC biomarker. Our findings suggest that REST_SSO suppresses tumorigenesis in neuroendocrine cancers by restoring REST function. This novel therapeutic approach holds promise for intractable neuroendocrine cancers such as SCLC and neuroendocrine PCa.© 2024 The Authors.