Construction of in vivo mRNA delivery systems
Construction of in vivo mRNA delivery systems
批准号:
10731953
负责人:
Yizhou Dong
金额:
$22.35万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-02-01 至 2027-01-31
中文摘要
项目总结
英文摘要
Project Summary
Cell-specific drug delivery represents one of the most important research areas in the field of drug delivery.
Particularly, there are formidable challenges for in vivo mRNA delivery. For example, therapeutic window for
current delivery systems is relatively narrow. A large number of cell types cannot be efficiently delivered in vivo.
Biodegradability of the delivery materials remains a concern. In order to address the challenges, the goals of our
research program are: 1) to develop diverse lipid derivatives; 2) to construct mRNA delivery systems; 3) to
examine the delivery efficiency, pharmacokinetics, and safety profile of these systems in animal models. In our
preliminary studies, we developed functionalized lipid-like nanoparticles for in vivo mRNA delivery and base
editing. The lead material was able to produce human factor VIII at a normal physiological level in hemophilia A
mice. The effective base editing was also achieved at low doses in mice. Meanwhile, we constructed vitamin
derived lipid nanoparticles, which enabled adoptive macrophage transfer for eliminating multidrug resistant (MDR)
bacteria in mouse models. Moreover, we showed promising mRNA delivery in other cell types, such as stem
cells and reproductive cells. Additionally, we systematically investigated the untranslated regions (UTRs) of
mRNAs in order to enhance protein production. Through a comprehensive analysis of endogenous gene
expression and de novo design of UTRs, we identified an optimal combination of 5’ and 3’ UTR, termed as
NASAR, which was significantly more efficient than the tested endogenous UTRs. These preliminary data
provide the scientific foundation to address the delivery challenges of mRNA-based therapeutics. In this proposal,
we propose four directions for mRNA delivery in vivo: (1) to optimize N1,N3,N5-tris(2-aminoethyl)benzene-1,3,5-
tricarboxamide (TT) lipid derivatives for hepatocytes delivery; (2) to investigate vitamin lipid derivatives for
macrophages delivery; (3) to develop glycolipid derivatives for stem cells delivery; (4) to conceive novel lipid
derivatives for reproductive cells delivery. We will prove the concept of cell-specific delivery systems in animal
models. Our research goal is to translate the innovations of this research strategy to develop better mRNA
delivery tools to treat diverse diseases.
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会议论文
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项目类别:
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资助金额:$77.81万
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财政年份:2022
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负责人:Yizhou Dong
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依托单位:
Construction of in vivo mRNA delivery systems
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批准号:10330667
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依托单位:
Construction of in vivo mRNA delivery systems
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Immunotherapy via engineered therapeutic programs in tumors using RNA
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项目类别:
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资助金额:$62.69万
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依托单位:
Immunotherapy via engineered therapeutic programs in tumors using RNA
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项目类别:
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资助金额:$65.35万
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Biodegradable nanoparticles, a genome editing platform to treat hemophilia
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项目类别:
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负责人:Yizhou Dong
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依托单位:
Biodegradable nanoparticles, a genome editing platform to treat hemophilia
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批准号:9916793
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项目类别:
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资助金额:$39.28万
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Cell-specific and multifunctional drug formulations for in vivo delivery
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Cell-specific and multifunctional drug formulations for in vivo delivery
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