Controlling DNA Condensation In Vitro

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DESCRIPTION (provided by applicant): The use of DNA as a therapeutic agent holds great promise for the treatment of genetic disorders and acquired diseases. To this end, nonviral (or artificial) gene delivery systems are attractive because they can circumvent some problems and risks associated with viral gene delivery. However, the efficiency of gene delivery in vivo by artificial systems is presently much lower than that achieved by viruses. It is widely appreciated that DNA condensation (or compaction) is an important component of most approaches to gene delivery. For example, packaging DNA into particles with dimensions smaller than 50 nm would greatly facilitate its diffusion through the intercellular matrix of tissues. Multivalent cations (e.g. spermidine) can cause DNA in solution to collapse into tightly packed toroidal and rod-like particles with overall dimensions of 100-200 nm. The ability to produce DNA particles with smaller and more uniform dimensions could be very useful in the development of nonviral approaches to gene delivery. The goal of this research is to develop methods for controlling the size and shape of particles into which DNA is condensed. Dr. Hud proposes the use of localized static bends, loops and ovals to nucleate condensation along otherwise linear DNA molecules upon their condensation by multivalent cations. It is expected that static loops will promote the formation of toroidal DNA particles with dimensions governed by the diameter of the loop. Alternatively, static oval structures may favor DNA compaction into rod-like particles where rod length is influenced by the length of the oval. This research should demonstrate the extent to which DNA static structures can be used to control DNA condensation. Dr. Hud's results will have direct implications on the feasibility of using static DNA structures in the development of nonviral gene delivery systems.