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.

项目摘要/摘要寡核苷酸遇到了几个生物制药困难，包括稳定性和交付问题作为非杂交活性，例如凝血病和免疫系统的不必要激活。我们已经开发了一种独特的寡核苷酸输送系统，称为PACDNA，它使用高密度奶瓶灌木聚合物可为寡核苷酸提供具有结合选择性。聚合物等于熵屏障，通过各种蛋白质（因此副作用）降低了对寡核苷酸的访问允许不受阻碍的杂交。这种新颖的策略不仅可以提高核酸酶稳定性，而且可以保留目标结合能力，并最大程度地减少靶向副作用，但也大大增强了等离子体体内药代动力学，组织保留和反义效力。我们目前的研究还表明 PACDNA的药物特性与奶瓶骨架密切相关。另外， PACDNA似乎具有唯一能够逃避抗载体自适应免疫性史的能力，这对需要长期/频繁给药的疗法。最后，pacDNA沉积到组织和器官中缺乏对皮肤，骨骼肌肉和心脏等成熟的分娩技术。这些令人惊讶和有能力的发现将成为下一个资金期间投资的基础，在此期间我们将使用与组合聚合物库一起探索PACDNA结构的性质空间特定的骨干组成和单体序列； 2）探针在PACDNA中的体内特性小鼠和非人类的私人模型以及它如何能够证明适应性免疫史； 3）探索 PACDNA的潜力创建第一/一流的疗法，利用其独特的优势使用相关的临床前疾病模型（后代）。我们预计这些对象的成就将对这类材料产生深厚的理解，并使我们更接近临床 PACDNA的评估。