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

Neuwelt, Edward A., Pagel, Michael A., Geller, Alfred and Muldoon, Leslie L. (1995) GENE REPLACEMENT THERAPY IN THE CENTRAL NERVOUS SYSTEM: VIRAL VECTOR MEDIATED THERAPY OF GLOBAL NEURODEGENERATIVE DISEASE.

Short Abstract:

This target article describes the current state of global gene replacement in the brain through the use of viral vectors and it assesses possible solutions to some of the many problems inherent in gene therapy for the central nervous system (CNS). Gene replacement therapy is a way to generate normal human proteins in deficient cells, making cures possible for certain genetically inherited enzyme deficiences, metabolic diseases, and cancers. The two major issues to be addressed are the delivery of genetic material to the brain and the expression of recombinant genetic material in CNS target cells. Focal inoculation of recombinant virions or other genetic vectors has limitations when there is global brain disease. A new blood-brain-barrier (BBB) disruption technique, in which hypertonic mannitol transiently shrinks the BBB endothelium, allows the passage of high molecular weight compounds and even viruses. CNS gene therapy will require a viral vector system that allows long-term, nontoxic gene expression in neurons or glial cells. Retroviral vectors have limitations in CNS gene replacement, although they are suitable for expressing recombinant genes in intracerebral grafts, or toxic genes in brain tumors. Mutant neurotropic viruses with reduced neurotoxicity (e.g., defective herpes simplex virus type 1 [HSV-1], the HSV-1 amplicon vector system we have developed, or adenovirus mutants) have potential for direct treatment of neurons. Injecting these vectors into rodent brains can lead to the stable expression of foreign genetic material in postmitotic neuronal cells. We discuss our BBB disruption delivery technique, our defective HSV-1 aplicon vector system, and our feline model for the neuronal lysosomal storage disorder Gm2-gangliosidosis (Sandhoff disease), which may prove to be a useful model system for CNS gene therapy.

Long Abstract:

This target article describes the current state of global gene replacement in the brain through the use of viral vectors and it assesses possible solutions to some of the many problems inherent in gene therapy for the central nervous system (CNS). Gene replacement therapy is a way to generate normal human proteins in deficient cells, making cures possible for certain genetically inherited enzyme deficiences, metabolic diseases, and cancers. The two major issues to be addressed are the delivery of genetic material to the brain and the expression of recombinant genetic material in CNS target cells. Focal inoculation of recombinant virions or other genetic vectors has limitations when there is global brain disease. A new blood-brain-barrier (BBB) disruption technique, in which hypertonic mannitol transiently shrinks the BBB endothelium, allows the passage of high molecular weight compounds and even viruses. CNS gene therapy will require a viral vector system that allows long-term, nontoxic gene expression in neurons or glial cells. Retroviral vectors have limitations in CNS gene replacement, although they are suitable for expressing recombinant genes in intracerebral grafts, or toxic genes in brain tumors. Mutant neurotropic viruses with reduced neurotoxicity (e.g., defective herpes simplex virus type 1 [HSV-1], the HSV-1 amplicon vector system we have developed, or adenovirus mutants) have potential for direct treatment of neurons. Injecting these vectors into rodent brains can lead to the stable expression of foreign genetic material in postmitotic neuronal cells. We discuss our BBB disruption delivery technique, our defective HSV-1 aplicon vector system, and our feline model for the neuronal lysosomal storage disorder Gm2-gangliosidosis (Sandhoff disease), which may prove to be a useful model system for CNS gene therapy.

Keywords:	adenovirus; blood-brain barrier; gene therapy; herpes virus; Hexosaminidase
Subjects:	BBS Special Issues: Controversies in Neuroscience: II - Neural Transplantation Psychology: Cognitive Psychology Neuroscience: Neuroanatomy Neuroscience: Neurochemistry Neuroscience: Neurology Neuroscience: Neurophysiology
ID code:	bbs00000514
Deposited by:	EA Neuwelt LL Muldoon on 02 May 2001