Engineering Effective Polymers to Enable Gene Based Therapies

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Molecular therapy utilizing nucleic acids offers an exciting approach over conventional drugs. Diseased organs can be better restored to normal state with the use of gene-based medicines derived from nucleic acids. The success, however, is absolutely dependent on the use of nucleic acid carriers, since nucleic acids alone cannot be internalized by cells due to their large size and anionic nature. Cationic polymers are safe carriers and they can readily neutralize nucleic acids and condense them into nanoparticles suitable for uptake. However, they suffer from low transfection efficiencies, short duration of activity and high toxicities. Overall goal of my research to create engineered' polymers that can self-assemble with nucleic acids to create nanoparticles ideal for cellular delivery. We have been engineering a class of gene carriers from lipid-substituted cationic polymers. Such polymers were found to create stable, self-assembled nanoparticles, enhancing delivery of the cargo into cells by as much as 100-fold. We identified several promising lipid substitutions and charted their beneficial in the delivery of particular types of nucleic acids in particular types of cells. No universal carrier design emerged in our past work, but we identified effective carriers for different types of cells. Our overall hypothesis is: amphiphilic polymers can be engineered from cationic polymers and lipids for controlled delivery and release of nucleic acids for specific cells, ultimately leading to improved functional outcomes in a safe manner. Three aims will be pursued for next generation carriers: Aim-1. To create tertiary' nanoparticles for superior delivery of nucleic acids. We recently discovered that adding a tertiary polyanion into nanoparticles improved the functional delivery. We will design superior tertiary nanoparticles by using in-house prepared polyanionic molecules with tailored features. Aim-2. To create multiple lipid-bearing polymers for delivery of nucleic acids to broader population of cells. We identified key lipid substituents effective for nucleic acid delivery in different patient cells. We propose to create hybrid' lipopolymers, where different lipid substituents will be methodically varied on the polymer backbone, to create universal' carriers capable of acting on wider source of cells. Aim-3. To determine functional performance of polymers for nucleic acid delivery. Using several in vitro models, we will investigate the functional performance of improved delivery systems from Aim-1 and -2. Systematic comparisons between current and new systems, and commercial reagents will be undertaken. My goal is to establish a foundation for polymer-guided delivery of genetic agents and develop functional materials for effective and safe delivery of nucleic acids. We envision the carriers to serve as R&D reagents in biomedical research enterprise as well as functional carriers to implement safe molecular therapies for human diseases.