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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：
10544115
负责人：
Ke Zhang
金额：
$ 40万
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 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10544115
关键词：
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 Immunization Immunocompetent In Vitro Inflammation Injections Intravenous KRAS2 gene Kidney Libraries Liver Lung MEKs Macaca fascicularis Malignant Epithelial Cell 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 Pharmacology Study Pharmacology and Toxicology Phase Plasma Polyethylene Glycols Polymers Pre-Clinical Model Property Proteins Publishing Refractory Research Ribonuclease H Safety Side Signal Pathway Structure Technology Therapeutic Therapeutic Agents Therapeutic Intervention Toll-like receptors Toxic effect Translating Translations Tumor Suppression Urine Vertebral column Xenograft Model acute toxicity alternative treatment base cancer cell cancer pharmacology clinical development cytokine dosage immunotoxicity improved in vivo inhibitor knock-down mortality mouse model mutant nanoparticle neglect nonhuman primate novel nucleic acid-based therapeutics patient derived xenograft model 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.

项目总结/文摘