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Principal Investigator: Yizhou Dong
Organization: OHIO STATE UNIVERSITY
Fiscal Year: 2022
Award: $190,245
Funding agency: National Institute of General Medical Sciences
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.
Terms: <3' Untranslated Regions><3'UTR><Address><Animal Model><Animal Models and Related Studies><Animals><Antihemophilic Factor><Area><Benzene><Benzol><Benzole><Biomedical Engineering><Blood Coagulation Factor VIII><Cell Body><Cells><Coagulation Factor VIII><Coagulation Factor VIIIc><Cyclohexatriene><Data><Disease><Disorder><Dose><Drug Delivery><Drug Delivery Systems><Drug Kinetics><Factor VIII><Factor VIII Deficiency><Factor VIII F8B><Formulation><Foundations><Gametes><Gene Expression><Germ Cells><Germ-Line Cells><Glycolipids><Goals><Hemophilia><Hemophilia A><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Human><Lead><Lipids><Liver Cells><Medicinal Chemistry><Messenger RNA><Mice><Mice Mammals><Modern Man><Multiple Anti-bacterial Drug Resistance><Multiple Anti-bacterial Drug Resistant><Multiple Antibacterial Drug Resistance><Multiple Antibacterial Drug Resistant><Multiple Bacterial Drug Resistance><Murine><Mus><Mφ><Pb element><Pharmaceutic Chemistry><Pharmaceutical Chemistry><Pharmaceutics><Pharmacokinetics><Pharmacy (field)><Physiologic><Physiological><Procoagulant Component><Production><Progenitor Cells><Proteins><Reproductive Cells><Research><Resistance to Multiple Anti-bacterial Drug><Resistance to Multiple Antibacterial Drug><Resistant to Multiple Anti-bacterial Drug><Resistant to Multiple Antibacterial Drug><Safety><Sex Cell><Specialty><System><Testing><Therapeutic><Thromboplastinogen><Translating><UTRs><Untranslated Regions><Vitamins><antihemophilic factor A><base><base editing><bio-engineered><bio-engineers><bioengineering><biological engineering><cell type><complex Blood-coagulation factor VIII><design><designing><heavy metal Pb><heavy metal lead><in vivo><initial cell><innovate><innovation><innovative><invention><lipid based nanoparticle><lipid nanoparticle><mRNA><mRNA delivery><macrophage><medical specialties><model of animal><model organism><mouse model><multi-drug resistant bacteria><multidrug resistant bacteria><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel therapeutics><novel therapy><platelet cofactor I><progenitor cell delivery><programs><sexual cell><stem cell delivery><stem cells><thromboplastinogen A><tool>