Developmental neurogenetic diseases can only be studied, and potentially treated, once systems to predictably deliver and express genes in neuronal cells are developed. We have utilized herpes simplex virus (HSV) as a vector for expressing genes in neuronal cells. This human DNA virus, for which about 90% of the U.S. population is seropositive, forms latent infections which persist for the lifetime of the individual. Using HSV derived vectors, we are studying the nervous system component of a lysosomal storage disease. Lysosomal storage in neurons results in severe mental retardation in most children with these diseases. Specifically, we will use a beta-lucuronidase-negative-mouse (gusmps/gusmps), with mucopolysaccharidosis (MPS) type VII (Sly disease), as an animal model. In the current grant period we have determined how to increase transgene expression by over 1000 fold from our initial vectors. We have also identified a problem in maintenance of gene expression and viral latency once the LAT gene (which contains the promoter of choice for transgene expression) is modified. We now wish to continue our studies by examining the factors that result in viral latent genome maintenance, to increase the number of corrected cells to bring vector correction to a level that will change the clinical disease. Specifically this will be achieved by determining how to insert a transgene into the LAT gene without disrupting the LAT latent genome maintenance function. The goal of these studies is to address the problem of treatment of neurogenetic diseases by developing a method of expressing genes in the nervous system in vivo using a ubiquitous human virus. These studies will also provide a method for studying gene regulation in neuronal cells in vivo.
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