Abstract 16919: Analysis of Astrocyte Activation and Reduction of Motor Deficits Following hSOX2 Gene Therapy Delivered Using PAMAM Dendrimer Nanomolecules in Ischemic Stroke

Abstract

PAMAM dendrimers are 3-dimensional nanomolecules which have the capability to deliverbiomolecules and gene therapy to the cells in vitro and in vivo . We have previously used the generation-4 surface-modified PAMAM dendrimers having 90% hydroxyl groups and 10% amine groups (G4-90/10) which are safe, cross the blood-brain barrier and deliver the biomolecules into the cells. In thecurrent study, we utilized G4-90/10 PAMAM dendrimers to deliver a gene therapy to the infarct in aischemic stroke brain in rats. Following an ischemic stroke, glial cells (such as astrocytes) are recruitedat the infarct region to perform maintenance functions, creating severe neuroinflammation. The goalof this study was to reprogram some of the astrocytes into neuronal lineage and repopulate the infarctregion. In addition, we also analyzed the temporal profile of astrocyte activation following ischemicstroke in the striatal and cortical regions to determine the time-point at which the maximum gliosisoccurs. This gives us a crucial timeline for treatment intervention to achieve astrocytereprogramming. We have used a transcription factor (hSOX2 gene), which was then delivered to thestroke brain in rats using the G4-90/10 dendrimers. Our results showed that the maximum glial cellactivation occurs in striatal and cortical regions on day 4 following ischemic stroke. Following genetherapy intervention, our initial analyses indicated that there was recovery from behavioral deficits inthe stroked rats compared to the vehicle-treated stroked rats and sham controls. Overall, these resultsshow that PAMAM dendrimers have significant potential delivering therapeutic molecules for treatingstroke and other neurological conditions. Support for this study was provided by the American Heart Association (18AIREA 33990094),Neuroscience program, the College of Medicine, department of Chemistry and Biochemistry, the JohnG. Kulhavi Professorship and the E. Malcolm Field and Gary Leo Dunbar Endowed Chair of Neuroscience at Central Michigan University.