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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

基本信息

批准号：
10896563
负责人：
Ke Zhang
金额：
$ 103.01万
依托单位：
PACDNA LLC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10896563
关键词：
Acceleration Address Animal Model Anti-Inflammatory Agents Antisense Oligonucleotides Area Under Curve Automobile Driving Binding Biological Availability Biological Products Blood Blood Coagulation Disorders Body Weight Cells Characteristics Chemicals Clinic Clinical Clinical Chemistry Coagulation Process Complement Data Deoxyribonucleases Development Drug Kinetics Exhibits Gene Expression Regulation Genes Goals Half-Life Human Immune system Immunity Immunocompetent Immunologic Stimulation In Vitro Inflammation Injections KRAS2 gene Kidney Libraries Liver Lung MEKs Macaca fascicularis Malignant Epithelial Cell Malignant Neoplasms Marketing Measurement Mediating Messenger RNA Methods Modality Modeling Modification Molecular Monitor Monkeys Morbidity - disease rate Mus Mutate Mutation Non-Small-Cell Lung Carcinoma Nucleic Acids Oligonucleotides Oncogenes Oncoproteins Pharmaceutical Preparations Pharmacologic Substance Pharmacology Study Pharmacology and Toxicology Phase Plasma Polyethylene Glycols Polymers Pre-Clinical Model Property Proteins Publishing Refractory Research Ribonuclease H Safety Side Signal Pathway Single-Stranded DNA Structure Technology Therapeutic Therapeutic Agents Therapeutic Intervention Toll-like receptors Toxic effect Translating Translational Repression Translations Tumor Suppression Urine Vertebral column Xenograft Model acute toxicity alternative treatment cancer cell clinical development cytokine dosage immunotoxicity improved in vivo inhibitor intravenous administration knock-down mortality mouse model mutant nanoparticle neglect nonhuman primate novel nucleic acid-based therapeutics patient derived xenograft model pharmacologic phosphodiester pre-clinical preclinical toxicity response safety assessment side effect single molecule small molecule small molecule inhibitor stem subcutaneous treatment strategy tumor uptake

项目摘要

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.

项目摘要/摘要突变形式的KRAS是人类肿瘤的关键驱动因素，但对治疗仍部分无效干预。经过三十多年的研究，只有一种抑制剂(索托拉西布)针对单一的突变(KRASG12C)已经上市。开发小分子KRAS抑制剂的难点提高了针对癌基因的替代方法的重要性。一种这样的策略涉及治疗性核酸，这使得耗尽难以处理的靶蛋白成为可能常规药物模式。我们已经开发出一种新形式的核酸疗法，称为布鲁塞尔™结合物，大大增强了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堆积，允许使用比传统方法低得多的剂量。这种结合物还通过以下方式抑制几乎所有与传统核酸药物有关的副作用减少不必要的核酸-蛋白质相互作用。这项提议的目标是为将这项技术转化为临床应用。在第一阶段，我们会优化布鲁斯希尔德™结合物，并使用一组非小细胞肺细胞和小鼠异种移植模型。在达到设定的数量里程碑时，我们将对共轭进行更相关的动物模型(原位和患者来源的异种移植模型)，并执行耐受性在小鼠和猴子身上的药代动力学研究(第二阶段)。这些研究将使我们能够继续进行在项目结束时提交IND文件。