胃癌腹膜转移与预后不良密切相关。在之前的临床前概念验证研究中，一种酰胺桥核酸 (AmNA) 修饰的反义寡核苷酸 (ASO)（命名为 ASO-4733）靶向编码突触结合蛋白 XIII (SYT13) 的基因，抑制形成突触结合蛋白所需的细胞功能。胃癌细胞腹膜转移。 ASO-4733 在小鼠异种移植模型腹腔内给药时取得了治疗效果。在这里，我们对 Syt13 缺陷小鼠进行了分析，以确定 ASO-4733 腹腔内给药的药代动力学和毒性。确定了 Syt13 缺陷对小鼠的影响。在食蟹猴和大鼠中进行了良好实验室规范毒性试验和 ASO-4733 腹内给药的毒代动力学。研究了 ASO-4733 静脉注射或腹腔注射给大鼠的药代动力学。Syt13 缺陷小鼠表现出正常的生殖、器官功能和运动功能。每周腹腔内施用 ASO-4733（125 mg/kg），相当于 4 周内估计临床剂量增加 50 倍，食蟹猴具有良好的耐受性。在大鼠中，每周腹腔内施用 ASO-4733 后观察到脱靶毒性（不可归因于杂交）。与静脉给药相比，腹腔给药后 ASO-4733 的血药浓度更低且上升更缓慢。ASO-4733 腹腔给药的临床前概况表明其适合进入胃癌腹膜转移患者的临床试验.© 2024。作者获得国际胃癌协会和日本胃癌协会的独家许可。

Peritoneal metastasis of gastric cancer is closely associated with dismal prognosis. In previous preclinical proof-of-concept studies, an amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotide (ASO), designated ASO-4733 that targets the gene encoding synaptotagmin XIII (SYT13), inhibited cellular functions required for the formation of peritoneal metastasis of gastric cancer cells. ASO-4733 achieved therapeutic effects when intra-abdominally administered to mouse xenograft models. Here, we conducted an analysis of Syt13-deficient mice to determine the pharmacokinetics and toxicity of intra-abdominal administration of ASO-4733.The effects of Syt13-deficiency in mice were determined. Good Laboratory Practice toxicity tests and the toxicokinetics of intra-abdominal administration of ASO-4733 were conducted in cynomolgus monkeys and rats. The pharmacokinetics of ASO-4733 administered intravenously or intra-abdominally to rats were investigated.Syt13-deficient mice exhibited normal reproduction, organ functions, and motor functions. Weekly intra-abdominal administration of ASO-4733 (125 mg/kg), corresponding to a 50-fold increase of the estimated clinical dose for 4 weeks, was well tolerated by cynomolgus monkeys. In rats, off-target toxicity (not attributable to hybridization) was observed after weekly intra-abdominal administration of ASO-4733. Blood concentrations of ASO-4733 were lower and rose more slowly after intra-abdominal administration compared with intravenous administration.The preclinical profile of intra-abdominal administration of ASO-4733 demonstrated its suitability for entry into clinical trials of patients with peritoneal metastasis of gastric cancer.© 2024. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.