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Gene therapy using viral vectors for acute neurologic insults

From the Department of Biological Sciences, Stanford University, and Department of Neurology and Neurological Sciences, Stanford University School of Medicine (Dr. Sapolsky); and the Department of Neurosurgery and Stanford Stroke Center (Dr. Steinberg), Stanford University School of Medicine, Stanford, CA.

Address correspondence and reprint requests to Dr. Sapolsky, Mail Code 5020, Stanford University, Stanford, CA 94305.

Enormous knowledge has emerged concerning the cellular and molecular events underlying necrotic neuron death after seizure, hypoxia–ischemia, or hypoglycemia. This has allowed the design of rational therapies to protect neurons at such times. One of the most exciting arenas of such interventions is the use of viral vectors to deliver neuroprotective genes. This review considers the progress in this nascent discipline. Neuroprotection has been demonstrated against a variety of in vitro and in vivo rodent models of necrotic insults with vectors overexpressing genes that target various facets of injury. These have included the energetic components, calcium excess, accumulation of reactive oxygen species, protein malfolding, inflammation, and triggering of apoptosis (i.e., programmed cell death) in a subset of cells. A number of caveats, subtleties, and pressing questions concerning this literature then are considered. These include whether these gene therapy interventions actually prevent, rather than merely delay, neuron death; the extent to which the effects of such vectors on neuronal cell biology is actually understood; the potential adverse effects of the use of such vectors; and whether sparing a neuron from death with one of these interventions spares function as well. Finally, we consider the likelihood of such gene therapy becoming relevant to clinical neurology in the near future.

Key words: Gene therapy—Hypoxia–ischemia—Seizure—Herpesvirus—Adenovirus—Energetics—Calcium—Heat-shock proteins—Reactive oxygen species—Necrosis—Apoptosis.