GENE REPLACEMENT THERAPY IN THE CENTRAL-NERVOUS-SYSTEM - VIRAL VECTOR-MEDIATED THERAPY OF GLOBAL NEURODEGENERATIVE DISEASE

This target article describes the current state of global gene replace ment in the brain using viral vectors and assesses possible solutions to some of the many problems inherent in gene therapy of the central n ervous system (CNS). Gene replacement therapy in the CNS is a potentia l means of producing a stable expression of normal human proteins in d eficient cells and thus curing certain genetically inherited enzyme de ficiencies and metabolic diseases as well as cancers. The two major is sues to be addressed in CNS gene replacement are the delivery of genet ic material to the brain and the expression of recombinant genetic mat erial in target cells within the CNS. Focal inoculation of recombinant virions or other genetic vectors has limitations in global CNS diseas e. A new approach is the blood-brain barrier (BBB) disruption techniqu e developed in this laboratory, in which hypertonic mannitol transient ly shrinks the BBB endothelium, allowing passage of high molecular wei ght compounds and even viruses. Gene therapy of the CNS will require a viral vector system that allows long-term, nontoxic gene expression i n neurons or glial cells. Retroviral vectors have limitations in CNS g ene replacement, although they are suitable for expressing recombinant genes in intracerebral grafts, or toxic genes in brain tumors. Using mutant neurotropic viruses with reduced neurotoxicity (such as defecti ve herpes simplex virus type I [HSV-1], the HSV-1 amplicon vector syst em we have developed, or adenovirus mutants) has potential for direct treatment of neurons. Injecting these vectors into rodent brains can l ead to stable expression of foreign genetic material in postmitotic ne uronal cells. We discuss our BBB disruption delivery technique, our de fective HSV-1 amplicon vector system, and our feline model for the neu ronal lysosomal storage disorder Gm2-gangliosidosis (Sandhoff disease) , which may prove to be a useful model system for CNS gene therapy.