Molecular brush-conjugated antisense oligonucleotide as a pan-KRAS depletion agent

分子刷偶联反义寡核苷酸作为泛 KRAS 耗竭剂

• 批准号: 10771051
• 负责人: Ke Zhang
• 金额: $ 5.5万
• 依托单位: PACDNA LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10771051
• 关键词: Acceleration; Animal Model; Antisense Oligonucleotides; Automobile Driving; Cells; Clinic; Drug Kinetics; Goals; Human; KRAS2 gene; Lung; Malignant Epithelial Cell; Malignant Neoplasms; Marketing; Methods; Modality; Molecular; Monkeys; Mus; Mutate; Mutation; Nucleic Acids; Oncogenes; Oncoproteins; Pharmaceutical Preparations; Pharmacology Study; Pharmacology and Toxicology; Phase; Plasma; Proteins; Refractory; Research; Structure; Technology; Therapeutic Agents; Therapeutic Intervention; Translating; Xenograft Model; dosage; improved; in vivo; inhibitor; mouse model; mutant; nonhuman primate; novel; nucleic acid-based therapeutics; patient derived xenograft model; pharmacologic; pre-clinical; side effect; small molecule; tumor; uptake

Project Summary/Abstract Mutant forms of KRAS are a key driver in human tumors but remain partially refractory to therapeutic intervention. After over three decades of research, only a single inhibitor (sotorasib) targeting a single mutation (KRASG12C) have reached market. The difficulty for developing small molecule KRAS inhibitors has heightened the importance of alternative methods targeting the oncogene. One such strategy involves therapeutic nucleic acids, which make it possible to deplete target proteins that are intractable to conventional drug modalities. We have developed a novel form of nucleic acid therapeutics, termed Brushield™ conjugate, which substantially enhances the antitumor activity of antisense oligonucleotides by elevating in vivo stability, accelerating cellular uptake, and improving plasma pharmacokinetics and tumor accumulation, allowing for a much lower dosage to be used compared to conventional methods. The conjugate also suppresses nearly all side effects associated with traditional nucleic acid drugs by reducing unwanted nucleic acid-protein interactions. The goal of this proposal is to lay the groundwork for translating the technology towards the clinic. In Phase I, we will optimize the structure of the Brushield™ conjugate, and enhance current indication using a panel of non-small cell lung cells and mouse xenograft models. Upon reaching set quantitative milestones, we will subject the conjugate to more relevant animal models (orthotopic and patient-derived xenograft models), and perform tolerability and pharmacokinetic studies in mice and monkeys (Phase II). These studies will allow us to pursue an IND filing at the end of the project.

项目概要/摘要 KRAS 突变形式是人类肿瘤的关键驱动因素，但仍然部分难以治疗 经过三十多年的研究，只有单一抑制剂（sotorasib）针对单一药物。 突变（KRASG12C）已上市 开发小分子KRAS抑制剂的难度。 针对癌基因的替代方法非常重要。 涉及治疗性核酸，这使得消除难以处理的靶蛋白成为可能 我们开发了一种新型的核酸疗法，称为“核酸疗法”。 Brushield™缀合物，可显着增强反义寡核苷酸的抗肿瘤活性 通过提高体内稳定性、加速细胞摄取、改善血浆药代动力学和 肿瘤积累，与传统方法相比，可以使用低得多的剂量。 该缀合物还通过以下方式抑制几乎所有与传统核酸药物相关的副作用： 减少不必要的核酸-蛋白质相互作用 该提案的目标是奠定基础。 为了将技术转化为临床，我们将在第一阶段优化结构。 Brushield™ 结合物，并使用一组非小细胞肺细胞和增强当前适应症 小鼠异种移植模型达到设定的定量里程碑后，我们将对缀合物进行处理。 更相关的动物模型（原位和患者来源的异种移植模型），并表现出耐受性 以及小鼠和猴子的药代动力学研究（第二阶段）。 项目结束时进行 IND 备案。