226. Developing a CNS-Specific Inflammatory Model To Investigate Gene Therapy/Inflammation Interactions in the Context of Neurodegeneration

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Top of pageAbstract Gene therapy represents a promising modality that may have clinical merit for preventing and/or treating a variety of neurodegenerative diseases, such as Alzheimer's disease (AD), Multiple Sclerosis (MS), and Parkinson's disease (PD). These disorders have been shown to include an inflammatory component that could significantly influence the efficacy and safety profiles of gene-based therapies. Direct gene transfer into an inflamed brain may lead to reduced therapeutic gene expression, or even worse, exacerbation of inflammation. To better assess these therapies, it is essential that they be tested in a more appropriate context. We have devised a mouse model in which inflammation can be triggered in the brain in a temporal and spatial manner. This mouse, designated NSE-IFNγ/lacZ XAT, harbors a transcription unit that contains the neuron-specific enolase (NSE) promoter, a loxP site-flanked strong transcriptional/translational stop cassette, the cDNA encoding the IFNγ gene, an internal ribosomal entry sequence (IRES), the β-galactosidase reporter gene (lacZ) and a 3' untranslated regulatory region. An inflammatory process can be induced focally upon somatic delivery of cre recombinase or widely via crossing to a cre recombinase-expressing transgenic mouse. We have confirmed cre-mediated expression of IFNγ (ELISA) and β-galactosidase (Galacto-Lite Assay and X-gal staining) in vitro. Additionally, we have successfully created founder mice and have been able to transmit the transgene in the F1 generation. We are currently assessing the functionality of the construct in vivo. Ongoing studies in our laboratory include use of this mouse to assess the effects of inflammation on direct herpes simplex virus amplicon gene transfer in the brain and to understand how inflammation influences the safety and efficacy of peripheral gene-based vaccination for AD. Although our investigative group is primarily interested in understanding AD-related inflammatory cascades, this model can be applied to numerous CNS and peripheral diseases.