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:
- 金额:$ 31.15万
- 依托单位:
- 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:
- 关键词:AcuteAddressAnimalsAntibodiesAntisense DNABenignBindingBiodistributionBiologicalBiological ProductsBlood CirculationBlood Coagulation DisordersBypassCatalytic RNACationsCellsCharacteristicsChemical StructureChemicalsChronicComplementary DNAComplexCongestiveDNADNA BindingDNA ProbesDNA SequenceDataDeoxyribonucleasesDevelopmentDiseaseDrug resistanceElectrostaticsEnvironmentEnzyme StabilityExhibitsFaceGene Therapy AgentGenesGeneticGenetic DiseasesGoalsHalf-LifeImmune responseImmune systemImmunizationIn VitroInsulinIntracellular TransportInvestigationKidneyKineticsLiposomesLiverMalignant NeoplasmsMicroRNAsModalityModelingModificationMolecularNeurodegenerative DisordersNucleic AcidsOligonucleotidesOutcome StudyPatternPattern recognition receptorPeptidesPermeabilityPharmaceutical PreparationsPolymersPropertyProteinsReticuloendothelial SystemSafetySerumSerum ProteinsSideSmall Interfering RNASpecificityStructureSystemTLR9 geneTherapeuticTherapeutic AgentsThermodynamicsThrombinToxic effectVertebral columnWorkaptamerbasebiological systemsbiomaterial compatibilitycancer celldensitydesignefficacy studyethylene glycolgene therapygene therapy clinical trialimmunogenicimmunogenicityimprovedin vivoinsightinterestknock-downmouse modelnanoparticlenovelnucleasenucleic acid deliverypathogenpharmacokinetics and pharmacodynamicspreservationpreventprotein expressionrefractory cancerside effectsingle moleculestemtumoruptake
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.
项目概要/摘要
使用寡核苷酸作为治疗剂存在重大兴趣,这面临着几个问题
生物制药困难,包括稳定性和递送问题,以及序列和/或化学问题
结构特异性、非杂交活性,例如凝血病和免疫刺激
系统。这些困难已通过寡核苷酸的化学修饰部分克服
主链或通过使用增强核酸酶的递送系统(通常是聚阳离子结构)
稳定性并提高交付效率。然而,这些方法要么带来新的挑战
(例如毒性和免疫原性),或无法充分解决所有负面方面。因此,一个
可以提高核酸酶稳定性、保留靶标结合能力、最大限度地减少所有脱靶的系统
效果,并改善生物分布仍然非常受追捧。我们的初步研究有
证明通过将 DNA 插入高密度刷状聚合物中可以实现 DNA 的“压缩”
环境,使 DNA 能够选择性地结合到互补的 DNA 链上,同时访问
各种蛋白质的作用是有限的。 DNA 与核酸酶、Toll 样受体 9 等蛋白质的结合
而凝血酶一般是无杂交副作用的第一步。因此,刷聚合物-
DNA 缀合物应该绕过寡核苷酸的许多副作用,并且有可能被
适用于基本上所有形式的寡核苷酸,即反义 DNA、siRNA、microRNA、适体、
核酶等,以改善其生物制药特性。这项研究的结果将是
新型生物相容性和非免疫刺激性寡核苷酸基因治疗剂,以及
对分子参数如何影响体内和体外的基本了解
特性。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Ke Zhang其他文献
Ke Zhang的其他文献
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{{ truncateString('Ke Zhang', 18)}}的其他基金
Development of a highly sensitive and specific POCT testing asthma triggering allergic IgE
开发高度敏感和特异的 POCT 测试哮喘触发过敏性 IgE
- 批准号:
10600767 - 财政年份:2023
- 资助金额:
$ 31.15万 - 项目类别:
Development of a highly sensitive and specific POCT testing asthma triggering allergic IgE
开发高度敏感和特异的 POCT 测试哮喘触发过敏性 IgE
- 批准号:
10817658 - 财政年份:2023
- 资助金额:
$ 31.15万 - 项目类别:
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
- 批准号:
10771051 - 财政年份:2022
- 资助金额:
$ 31.15万 - 项目类别:
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
- 批准号:
10544115 - 财政年份:2022
- 资助金额:
$ 31.15万 - 项目类别:
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
- 批准号:
10896563 - 财政年份:2022
- 资助金额:
$ 31.15万 - 项目类别:
Targeting Oncogenic KRAS with Brush-Architectured Poly(ethylene glycol)-DNA Conjugates
使用刷状结构的聚(乙二醇)-DNA 缀合物靶向致癌 KRAS
- 批准号:
10430047 - 财政年份:2020
- 资助金额:
$ 31.15万 - 项目类别:
Targeting Oncogenic KRAS with Brush-Architectured Poly(ethylene glycol)-DNA Conjugates
使用刷状结构的聚(乙二醇)-DNA 缀合物靶向致癌 KRAS
- 批准号:
10653706 - 财政年份:2020
- 资助金额:
$ 31.15万 - 项目类别:
Targeting Oncogenic KRAS with Brush-Architectured Poly(ethylene glycol)-DNA Conjugates
使用刷状结构的聚(乙二醇)-DNA 缀合物靶向致癌 KRAS
- 批准号:
10210369 - 财政年份:2020
- 资助金额:
$ 31.15万 - 项目类别:
Targeting Oncogenic KRAS with Brush-Architectured Poly(ethylene glycol)-DNA Conjugates
使用刷状结构的聚(乙二醇)-DNA 缀合物靶向致癌 KRAS
- 批准号:
10035113 - 财政年份:2020
- 资助金额:
$ 31.15万 - 项目类别:
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:
10659672 - 财政年份:2017
- 资助金额:
$ 31.15万 - 项目类别:
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