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

• 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
• 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

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.

项目摘要/摘要 使用寡核苷酸作为治疗剂的重要兴趣，面临几种 生物制药难度，包括稳定性和交付问题，以及序列 - 和/或化学 结构特异性的非杂交活性，例如凝血病和免疫刺激 系统。这些困难部分被寡核苷酸的化学修饰克服了 主链或使用递送系统（通常是多阳化结构），从而增强核酸酶 稳定并提高交付效率。但是，这些方法要么引起新的挑战 （例如毒性和免疫原性），或者无法充分解决所有负面方面。因此， 可以改善核酸酶稳定性，保留目标结合能力的系统，最大程度地减少所有目标 效果和改善生物分布仍然是非常有意义的。我们的初步研究 证明DNA的“压实”可以通过将其插入高密度的刷子聚合物来实现 环境，使DNA能够选择性地结合完整的DNA链，同时访问 各种蛋白质受到限制。 DNA与蛋白质（例如核体）的结合，Toll样受体9， 凝血酶通常是非杂交副作用的第一步。因此，刷聚合物 - DNA结合物应绕过寡核苷酸的许多副作用，并具有BE 应用于所有形式的寡核苷酸，即反义DNA，siRNA，microRNA，Aptamers， 核酶等以改善其生物药物特征。这项研究的结果将是 新的生物相容性和非免疫刺激性寡核苷酸基因治疗剂以及 对其分子参数如何影响其体内和体外的基本了解 特性。