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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：
10259829
负责人：
Ke Zhang
金额：
$ 31.15万
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 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10259829
关键词：
Acute Address Animals Antibodies Antisense DNA Benign Binding Biodistribution Biological Biological Products Blood Circulation Blood Coagulation Disorders Bypass Catalytic RNA Cations Cells Characteristics Chemical Structure Chemicals Chronic Complementary DNA Complex Congestive DNA DNA Binding DNA Probes DNA Sequence Data Deoxyribonucleases Development Disease Drug resistance Electrostatics Environment Enzyme Stability Exhibits Face Gene Therapy Agent Genes Genetic Genetic Diseases Goals Half-Life Immune response Immune system Immunization In Vitro Insulin Intracellular Transport Investigation Kidney Kinetics Liposomes Liver Malignant Neoplasms MicroRNAs Modality Modeling Modification Molecular Neurodegenerative Disorders Nucleic Acids Oligonucleotides Outcome Study Pattern Pattern recognition receptor Peptides Permeability Pharmaceutical Preparations Polymers Property Proteins Reticuloendothelial System Safety Serum Serum Proteins Side Small Interfering RNA Specificity Structure System TLR9 gene Therapeutic Therapeutic Agents Thermodynamics Thrombin Toxic effect Vertebral column Work aptamer base biological systems biomaterial compatibility cancer cell density design efficacy study ethylene glycol gene therapy gene therapy clinical trial immunogenic immunogenicity improved in vivo insight interest knock-down mouse model nanoparticle novel nuclease nucleic acid delivery pathogen pharmacokinetics and pharmacodynamics preservation prevent protein expression refractory cancer side effect single molecule stem tumor uptake

项目摘要

Project Summary/Abstract Significant interests exist for using oligonucleotides as therapeutic agents, which face several biopharmaceutical difficulties, including stability and delivery issues, and sequence- and/or chemical structure-specific, non-hybridization activities, such as coagulopathies and stimulation of the immune system. These difficulties have been in part overcome by chemical modification of the oligonucleotide backbone or by using delivery systems (oftentimes polycationic structures), which enhance nuclease stability and improve delivery efficiency. However, these approaches either give rise to new challenges (e.g. toxicity and immunogenicity), or cannot adequately address all of the negative aspects. Therefore, a system that can improve nuclease stability, preserve target-binding capability, minimize all off-target effects, and improve biodistribution is still very much sought after. Our preliminary studies have demonstrated that “compaction” of DNA can be achieved by inserting it into a high-density brush polymer environment, which enables the DNA to bind selectively to a complementary DNA strand, while access by various proteins is limited. The binding of DNA with proteins such as nucleases, toll-like receptor 9, and thrombin is generally the first step to non-hybridization side effects. Therefore, the brush polymer- DNA conjugates should bypass many of the side effects of oligonucleotides and has the potential to be applied to essentially all forms of oligonucleotides, i.e. antisense DNA, siRNA, microRNA, aptamers, ribozymes, etc., to improve their biopharmaceutical characteristics. The outcome of this study would be a new class of biocompatible and non-immunostimulatory oligonucleotide-based gene therapy agents, and a fundamental understanding of how its molecular parameters can impact its in vivo and in vitro properties.

项目总结/文摘