Dr. Jeoung Soo Lee
Assistant Professor of Bioengineering
Physical trauma or ischemia results in significant damage to the central nervous system (CNS). The regenerative capacity of the injured adult CNS is extremely limited, due to both extrinsic microenvironmental factors and intrinsic, age-related changes in plasticity. With few existing therapies available, CNS injury commonly leads to permanent loss of cognitive, motor, and/or sensory function.
The objective of this proposal is to gather critical preliminary data to provide improved evidence of feasibility and enable the development of a competitive R01 submission applying this drug delivery technology for the treatment of traumatic brain injury. In aim 1, we will synthesize and characterize the physical/chemical properties of rolipram-loaded PGP-Ab/siRNA complex nanoparticles as a drug and nucleic acid delivery carrier. In aim 2, we will evaluate the specificity, transfection efficiency and cytotoxicity of PGP-Ab/siRNA complex nanoparticle using biotin conjugated siRNA in rat DRG neurons in vitro. In aim 3, we will evaluate the distribution of PGP-Ab/siRNAs complex nanotherapeutics in a rat direct cortical impact model.
In preliminary studies, we have described the synthesis and characterization of PLGA-graft-PEI and shown its ability to deliver siRNA to primary CNS neurons with high transfection efficiency and minimal cytotoxicity. Based on this data, we prepared a R21 application to NIH/NINDS with the goal of increasing axonal regeneration following spinal cord injury using antibody-targeted polymeric micelles for combinatorial delivery of siRNA targeting common intracellular signaling pathways activated by growth inhibiting molecules and the phosphodiesterase inhibitor, rolipram. This proposal reached the 17th percentile on its first resubmission, but its score increased on the final submission due to several persistent reviewer concerns we were not able to effectively address.
The long-term goal of this project is to develop biomaterial-based drug delivery systems capable of improving CNS regenerative capacity, primarily through increasing plasticity. The approach is based on polymeric micelle nanotherapeutics capable of combinatorial delivery of different drugs targeting the multiple pathophysiological aspects of CNS trauma. Polymeric micelles are formed from graft copolymers of poly (lactide-co-glycolide) [PLGA] and polyethlyenimine [PEI]. In aqueous solution, the PLGA core provides a reservoir for incorporation of hydrophobic drugs, while the PEI shell can electrostatically bind nucleic acid therapeutics such as plasmid DNA, siRNA, and microRNA. In addition, conjugation of antibodies or specific ligands to the PEI shell offers a basis for neuron-specific targeting.
The specific aims are as follows: