Nucleic acid modulators and theranostics for ADAR
ADAR 的核酸调节剂和治疗诊断
基本信息
- 批准号:10490352
- 负责人:
- 金额:$ 11.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-18 至 2023-06-15
- 项目状态:已结题
- 来源:
- 关键词:ADAR1AcetylgalactosamineAddressAdenosineAgonistAlbuminsBiologicalBiological ProcessBiologyCellsChimera organismClinicalCyclic GMPDNADiseaseDrug KineticsEngineeringEnvironmentGTP-Binding Protein alpha Subunits, GsGuide RNAGuidelinesHumanImmunotherapyIndividualInosineInterferon Type IInterferonsLigandsLuciferasesMediatingMedicineMessenger RNAMetastatic MelanomaMolecularMutationNucleic AcidsOligonucleotidesOutcomePathogenicityPeptidesRNARNA BindingRNA EditingReporterSafetySmall Interfering RNATestingThrombophiliaTimeTissuesTreatment Efficacyadenosine deaminaseaptamerbasebiological systemsbioluminescence imagingdesignefficacy testingfactor V Leidengene therapyimprovedin vivolipid nanoparticlemelanomamouse modelnanonanoparticleneoplastic cellnovelnucleic acid deliverynucleic acid-based therapeuticspilot testscaffoldspatiotemporalstoichiometrysuccesstargeted deliverytheranosticstooltrafficking
项目摘要
Project Summary
The objectives of this MIRA application are to 1) in vivo profiling of heterogeneous Adenosine deaminase acting
on RNA (ADAR) using RNA nano-reporters as a tool to understand ADAR biology and guide the design of ADAR-
based therapy; 2) promoting endogenous ADAR modulation using chimeric ADAR aptamer-gRNA (guide RNA)
and a type I interferon (IFN-I)-activating DNA oligonucleotide that induces ADAR1; 3) targeted delivery of
albumin-hitchhiking DNA/RNA for endogenous ADAR-based gene therapy and immunotherapy; and 4) pilot
testing of these theranostics in mouse models of Factor V Leiden (FVL) thrombophilia and metastatic melanoma.
ADAR mediates RNA Adenosine-to-Inosine editing in metazoans. ADAR is an intriguing endogenous RNA editor
for the gene therapy of diseases caused by pathogenic G->A mutations, such as FVL thrombophilia; moreover,
ADAR1 inhibition in tumor cells sensitizes their immunotherapy. However, ADAR levels are highly
heterogeneous and dynamic across individuals, tissues, and cell environments, making it pivotal for
spatiotemporal ADAR profiling to study ADAR biology and design personalized ADAR-based therapy. To this
end, we will develop and test an ADAR reporter for non-invasive real-time ADAR profiling in vivo, using an ADAR-
activatable split luciferase mRNA reporter followed by bioluminescence imaging. Further, the often low
endogenous ADAR levels limit ADAR editing efficacy, which impedes ADAR biological discovery and theranostic
applications. To address this challenge and promote the RNA editing efficacy of endogenous ADAR, we will
study two strategies: 1) using ADAR aptamer-gRNA chimera to promote ADAR binding and editing of RNA; and
2) using our novel IFN-I-activating DNA agonist for cyclic GMP-AMP synthase to elevate ADAR levels and
promote ADAR modulatory efficacy. All these nucleic acid theranostics, such as aptamers, siRNA, and mRNA,
hold great potential to reshape human medicine. Yet, naked DNA/RNA has limited clinical success thus far,
largely due to poor pharmacokinetics (PK) and inability to enter cells, calling for mechanistic understanding and
manipulation of the interactions between biological systems and DNA/RNA. Previously, we developed a
molecular albumin hitchhiker and nanoparticles that promoted the PK and delivery of nucleic acids by up to 200
folds. Here, we will use lipid nanoparticles to deliver mRNA reporters for in vivo ADAR profiling; we will study
targeted delivery of albumin-hitchhiking ADAR nucleic acid therapeutics, including aptamer-gRNA chimera for
FVL thrombophilia gene therapy and siRNAADAR1 for advanced melanoma immunotherapy. We will engineer
nucleic acid scaffolds to co-deliver synergistic nucleic acids at defined stoichiometry. We will delineate the
engineering principles to improve the PK, (co-)delivery, safety, and therapeutic efficacy, and promote intracellular
trafficking and target interaction; we will study the impact of targeting ligands (aptamers, peptides, N-
acetylgalactosamine) on these outcomes. Overall, these studies would establish the guidelines to design nucleic
acid tools to understand and modulate ADAR biology, and design personalized ADAR therapy.
1
项目摘要
该MIRA应用的目的是:1)异构腺苷脱氨酶作用的体内图谱
用RNA纳米记者作为了解ADAR生物学和指导ADAR设计的工具
基础治疗;2)利用嵌合ADAR适配子-gRNA(引导RNA)促进内源性ADAR调节
和一种I型干扰素(IFN-I)激活DNA寡核苷酸,可诱导ADAR1;3)靶向递送
白蛋白搭便车DNA/RNA用于内源性ADAR基因治疗和免疫治疗;以及4)飞行员
在因子V莱顿(FVL)血栓形成和转移性黑色素瘤小鼠模型中测试这些治疗药物。
Adar在后生动物中介导RNA腺苷到肌苷的编辑。Adar是一位耐人寻味的内源性RNA编辑
用于致病性G-GT;A突变引起的疾病的基因治疗,如FVL血栓形成症;此外,
抑制肿瘤细胞中的ADAR1使其免疫治疗变得敏感。然而,ADAR水平很高
跨个人、组织和细胞环境的异构性和动态化,使其成为
研究ADAR生物学和设计个性化的基于ADAR的治疗。对这件事
最后,我们将开发和测试用于体内非侵入性实时ADAR分析的ADAR报告器,使用ADAR-
可激活的裂解荧光素酶信使核糖核酸报告后进行生物发光成像。此外,通常情况下,
内源性ADAR水平限制了ADAR编辑效率,这阻碍了ADAR的生物发现和治疗
申请。为了应对这一挑战并促进内源性ADAR的RNA编辑功效,我们将
研究两种策略:1)利用ADAR适体-gRNA嵌合体促进ADAR与RNA的结合和编辑;
2)使用我们的新型干扰素-I激活DNA激动剂的环GMP-AMP合成酶,以提高ADAR水平和
促进ADAR调节功效。所有这些核酸共振子,如适配子、siRNA和mRNA,
拥有重塑人类医学的巨大潜力。然而,到目前为止,裸露的DNA/RNA在临床上的成功有限,
主要是由于较差的药代动力学(PK)和无法进入细胞,需要从机制上理解和
操纵生物系统与DNA/RNA之间的相互作用。之前,我们开发了一种
分子白蛋白搭便车和纳米颗粒,促进PK和核酸递送高达200
折叠。在这里,我们将使用脂质纳米颗粒来传递用于体内ADAR分析的信使核糖核酸;我们将研究
靶向递送白蛋白搭便车ADAR核酸疗法,包括适体-gRNA嵌合体
FVL亲血栓基因治疗和siRNAADAR1用于晚期黑色素瘤免疫治疗。我们将进行工程设计
以确定的化学计量比协同传递协同核酸的核酸支架。我们将勾勒出
改善PK、(联合)传递、安全性和治疗效果的工程原则,并促进细胞内
贩运和靶相互作用;我们将研究靶向配体(适配子、肽、N-
乙酰半乳糖胺)对这些结果的影响。总体而言,这些研究将建立设计核子的指导方针
ACID工具,用于了解和调节ADAR生物学,并设计个性化的ADAR疗法。
1
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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Guizhi Zhu其他文献
Guizhi Zhu的其他文献
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{{ truncateString('Guizhi Zhu', 18)}}的其他基金
Lymph node-targeted codelivery of albumin-binding peptide antigens and di-adjuvant for melanoma combination immunotherapy
用于黑色素瘤联合免疫治疗的白蛋白结合肽抗原和双佐剂的淋巴结靶向共递送
- 批准号:
10522591 - 财政年份:2022
- 资助金额:
$ 11.39万 - 项目类别:
Lymph Node-Targeted Codelivery of Albumin-Binding Peptide Antigens and Di-Adjuvant for Melanoma Combination Immunotherapy
用于黑色素瘤联合免疫治疗的白蛋白结合肽抗原和双佐剂的淋巴结靶向共递送
- 批准号:
10884052 - 财政年份:2022
- 资助金额:
$ 11.39万 - 项目类别:
Nucleic acid modulators and theranostics for ADAR
ADAR 的核酸调节剂和治疗诊断
- 批准号:
10276650 - 财政年份:2021
- 资助金额:
$ 11.39万 - 项目类别:
Administrative Supplement (Equipment): Nucleic acid modulators and theranostics for ADAR
行政补充(设备): ADAR 的核酸调节剂和治疗诊断
- 批准号:
10582378 - 财政年份:2021
- 资助金额:
$ 11.39万 - 项目类别:
Nucleic acid modulators and theranostics for ADAR
ADAR 的核酸调节剂和治疗诊断
- 批准号:
10682512 - 财政年份:2021
- 资助金额:
$ 11.39万 - 项目类别:
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