Making Oligonucleotides Better Biopharmaceuticals by Steric Protection

通过空间保护使寡核苷酸成为更好的生物制药

基本信息

批准号：
10659672
负责人：
Ke Zhang
金额：
$ 48.6万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659672
关键词：
Adopted Affect Antisense Oligonucleotides Area Benign Binding Binding Proteins Biodistribution Biological Availability Biological Products Blood Blood Coagulation Disorders Brain Cell Communication Cells Characteristics Chemicals Clinical Clinical Trials Cytoplasm DNA DNA Structure Deposition Development Disease Disease model Dose Drug Kinetics Endosomes Endowment Enzyme Stability Exhibits Face Frequencies Funding Genes Genetic Diseases Goals Heart Hydrophobicity Immune system Immunologic Stimulation Injections Investigation KRAS2 gene Kinetics Libraries Lipids Liver Machine Learning Messenger RNA Metabolic Diseases Modality Modeling Modification Molecular Mus Muscle Non-Small-Cell Lung Carcinoma Nuclear Nucleic Acids Oligonucleotides Organ Peptides Pharmaceutical Preparations Philosophy Plasma Plasma Enhancement Polymers Pre-Clinical Model Progeria Property Proteins RNA RNA Splicing Renal clearance function Ribonuclease H Safety Side Site Skeletal Muscle Skin Structure Syndrome System Technology Therapeutic Therapeutic Agents Thermodynamics Tissues Toxic effect Transcriptional Regulation Transfection Translational Repression Treatment Efficacy Tumor Suppression United States Food and Drug Administration Untranslated RNA Vertebral column Virus Diseases Xenograft Model adaptive immunity combinatorial cost delivery vehicle density design dosage efficacy evaluation epigenetic regulation fomivirsen immune activation improved in vivo insight learning materials mRNA Precursor monomer nanoparticle neglect nonhuman primate novel novel strategies nuclease nucleic acid delivery nucleobase pharmacologic pre-clinical preservation research clinical testing side effect simulation stem tool uptake vector

项目摘要

Project Summary/Abstract Oligonucleotides face several biopharmaceutical difficulties, including stability and delivery issues as well as non-hybridization activities such as coagulopathy and unwanted activation of the immune system. We have developed a unique oligonucleotide delivery system, termed pacDNA, which uses a high-density bottlebrush polymer to provide oligonucleotides with binding selectivity. The polymer amounts to an entropic barrier, reducing access to the oligonucleotide by various proteins (and thus side effects) but still allows for unhindered hybridization. This novel strategy not only improves nuclease stability, preserves target-binding capability, and minimizes off-target side effects, but also massively enhances plasma pharmacokinetics, tissue retention, and antisense potency in vivo. Our current studies also reveal that the pacDNA’s pharmacological properties are intimately related to the bottlebrush backbone. In addition, the pacDNA appears to be uniquely capable of evading anti-carrier adaptive immunity, which is useful for therapies that requires long-term/frequent dosing. Finally, the pacDNA deposits into tissues and organs that lack mature delivery technologies for, such as the skin, the skeletal muscle, and the heart. These surprising and enabling discoveries will be the basis for investigations in the next funding period, in which we will 1) explore the property space of the pacDNA structure using a combinatorial polymer library with specific backbone compositions and monomer sequences; 2) probe in vivo properties of the pacDNA in mouse and non-human primate models and how it is able to evade adaptive immunity; and 3) explore the potential of pacDNA to create first/best-in-class therapies that take advantage of its unique strengths using a relevant preclinical disease model (progeria). We anticipate that accomplishment of these objectives will yield significant fundamental understanding of this class of materials and bring us much closer to clinical evaluation of pacDNA.

项目概要/摘要寡核苷酸面临多种生物制药困难，包括稳定性和递送问题如凝血病和免疫系统不必要的激活等非杂交活动。开发了一种独特的寡核苷酸递送系统，称为 pacDNA，它使用高密度瓶刷聚合物以提供具有结合选择性的寡核苷酸。熵屏障，减少了各种蛋白质对寡核苷酸的接触（从而减少了副作用），但仍然这种新颖的策略不仅提高了核酸酶的稳定性，而且保留了核酸酶的稳定性。目标结合能力，最大限度地减少脱靶副作用，同时还大大增强了血浆我们目前的研究还表明，体内的药代动力学、组织保留和反义效力。 pacDNA 的药理学特性与洗瓶刷骨架密切相关。 pacDNA 似乎具有独特的能力来逃避抗携带者适应性免疫，这对于需要长期/频繁给药的疗法最后，pacDNA 沉积到组织和器官中。缺乏成熟的输送技术，例如皮肤、骨骼肌和心脏。令人惊讶和有利的发现将成为下一个资助期调查的基础，其中我们将 1) 使用组合聚合物库探索 pacDNA 结构的属性空间特定主链组成和单体序列；2) 探测 pcDNA 的体内特性小鼠和非人类灵长类动物模型以及它如何逃避适应性免疫；3）探索 pacDNA 具有创造首创/一流疗法的潜力，利用其独特的优势我们预计这些目标的实现将是一个相关的临床前疾病模型（早衰症）。对此类材料产生重要的基础了解，并使我们更接近临床 pacDNA 的评估。