Lysosomal storage diseases affect multiple tissues. The systemic disease can be corrected by a variety of methods. However, because of the relative impermeability of the blood-brain barrier, correction of the CNS deficits will require delivery of the enzyme directly to the CNS. Based on our prior work with adenoviruses and non-viral vector systems, and our recent work with MMLV- and HIV-based vectors, novel experiments with lentivirus vectors are proposed in the MPS VII model of lyososomal storage disease. Trough the experiments outlined in this proposal we will test if 1) secretion of beta-glucuronidase into CSF results in enzyme penetration into the parenchyma and correction of the disease, 2) if beta-glucuronidase enzyme or the recombinant lentivirus vector can be induced to enter brain from CSF, 3) what cell types are infected after intraparenchymal injections of lentivirus vectors in normal and diseased mouse brain, and if the cell type infected affects the persistence of expression, and, in the MPS VII mouse, correction, 4) how delivery of beta-glucuronidase from CSF or parenchyma cells impacts on behavioral measures in the MPS VII model, and 5) if lentivirus vectors can be modified for transduction of vascular endothelium. The results of our studies will have important implications for CNS disease resulting from other storage deficiencies and for other vector systems.
Showing the most recent 10 out of 33 publications
