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Novel strategy for protecting neurons from injury in stroke

Institution: Stanford University
Investigator(s): Robert Sapolsky, Ph.D.
Award Cycle: 1999 (Cycle 8) Grant #: 8RT-0073 Award: $742,809
Subject Area: Cardiovascular Disease
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
One of the most serious consequences of chronic tobacco use is cerebrovascular disease, specifically stroke damage to the nervous system. One of the tragedies of neurological disease is that, in the vast majority of cases, a neuron lost to disease cannot be replaced. This increases the pressure to find therapies that will prevent an endangered neuron from dying.

Knowledge has emerged in the last decade regarding how a neuron dies after an insult like a stroke, uncovering what the cells “Achilles’ heels” are. This knowledge has made possible a strategy of introducing protective genes into neurons that might protect them from stroke damage. For complex reasons, the most plausible way of conducting such “gene therapy” is to use safe, artificial versions of viruses that preferentially infect neurons (such as herpes virus) as “vectors” for delivering protective genes. My laboratory has been one of those pioneering gene therapy techniques in the nervous system, using such viral vectors. We have reported the protective effects of a handful of genes, using both tissue culture and animal models of stroke, seizure and hypoglycemia.

In this proposal, we wish to expand into our next generation of genes to study, examining their ability to protect neurons in tissue culture from models of stroke-like damage; success in this area would be a precursor to then using whole animal models of injury. The new genes (and their protein products) that we wish to study are as follows: (a) during periods of injury or challenge, cells activate a family of genes that code for “stress proteins” that aid their survival, and we wish to study the protective effects of the stress protein gene that is most dramatically activated during a neuronal crisis. (b) We have previously documented the neuroprotective potential of a gene coding for an “antiapoptotic protein” (one that protects against programmed cell death following strokes); a new version of this gene has recently been identified, coding for a protein that should be even more protective than its cousin that we have studied, in that it works for a far longer period of time. (c) One of the main consequences of stroke damage is the generation of oxygen radicals, and we will be studying the protective effects of a family of antioxidant enzymes. In the experiments outlined, we will not only determine whether a viral vector expressing one of these genes does indeed reduce neuron death, but HOW such protection occurs, examining the intervening cell biology.

Gene therapy within the nervous system is in its infancy as a discipline, and techniques are far from being ready for clinical use. However, studies such as these are important ones for moving it in that direction. When usable in a clinical setting such approaches may be of enormous benefit.

Final Report
One of the most serious consequences of chronic tobacco use is cerebrovascular disease, specifically stroke damage to the nervous system. One of the tragedies of neurological disease is that, in the vast majority of cases, a neuron lost to disease cannot be replaced. Thus, this increases the pressure to find therapies that will prevent an endangered neuron from dying.

Knowledge has emerged in the last decade regarding how a neuron dies after an insult like a stroke, uncovering what the cell’s “Achilles’ heels” are. This knowledge has made possible a strategy of introducing protective genes into neurons that might protect them from stroke damage. For complex reasons, the most plausible way of conducting such “gene therapy” is to use safe, artificial versions of viruses that preferentially infect neurons (such as herpes virus) as “vectors” for delivering protective genes. My laboratory has been one of those pioneering gene therapy techniques in the nervous system, using such viral vectors. We have reported the protective effects of a handful of genes, using both tissue culture and animal models of stroke, seizure and hypoglycemia.

In this proposal, we wish to expand into our next generation of genes to study, examining their ability to protect neurons in tissue culture from models of stroke-like damage; success in this area would be a precursor to then using whole animal models of injury. The new genes (and their protein products) that we wish to study are as follows: a) during periods of injury or challenge, cells activate a family of genes that code for “stress proteins” that aid their survival, and we wish to study the protective effects of the stress protein gene that is most dramatically activated during a neuronal crisis. b) We have previously documented the neuroprotective potential of a gene coding for an “antiapoptotic protein” (one that protects against programmed cell death following strokes); a new version of this gene has recently been identified, coding for a protein that should be even more protective than its cousin that we have studied, in that it works for a far longer period of time. c) One of the main consequences of stroke damage is the generation of oxygen radicals, and we will be studying the protective effects of a family of antioxidant enzymes. In the experiments outlined, we will not only determine whether a viral vector expressing one of these genes does indeed reduce neuron death, but how such protection occurs, examining the intervening cell biology.

Gene therapy within the nervous system is in its infancy as a discipline, and techniques are far from being ready for clinical use. However, studies such as these are important ones for moving it in that direction. When usable in a clinical setting such approaches may be of enormous benefit.
Publications

Neuroprotection with herpes simplex viral vectors expressing virally derived anti-apoptotic agents
Periodical: Brain Research Index Medicus:
Authors: Roy M, Hom J, Sapolsky R ART
Yr: 2001 Vol: 901 Nbr: Abs: Pg: 12

Effect of gp120 on glutathione peroxidase activity in cortical cultures and the interaction with steroid hormones.
Periodical: Journal of Neurochemistry Index Medicus:
Authors: Brooke S, McLaughlin J, Cortopassi K, and Sapolsky R ART
Yr: 2002 Vol: 81 Nbr: Abs: Pg: 277

The overexpression of HSP72 after the induction of experimental stroke protects neurons from ischemic damage.
Periodical: Journal of Cerebral Blood Flow and Metabolism Index Medicus:
Authors: Hoehn B, Ringer T, Xu L, Giffard R, Sapolsky R, Steinberg G., and Yenari M ART
Yr: 2001 Vol: 21 Nbr: Abs: Pg: 1303

Neuroprotective effects of bcl-2 overexpression in hippocampal cultures: Interactions with pathways of oxidative damage.
Periodical: Journal of Neurochemistry Index Medicus:
Authors: Howard S, Bottino C. Brooke S, Cheng E, Giffard R, and Sapolsky R ART
Yr: 0 Vol: Nbr: Abs: Pg:

Gene transfer of HSP72 protects CA1 neurons from global ischemia: influence of bel-2.
Periodical: Annals of Neurology Index Medicus:
Authors: Kelly S, Zhang Z, Zhao H, Xu L, Giffard R, Sapolsky R, Yenari M, and Steinberg G ART
Yr: 0 Vol: Nbr: Abs: Pg:

Disruptive effects of glucocorticoids on glutathione peroxidase biochemistry in hippocampal cultures.
Periodical: Journal of Neurochemistry Index Medicus:
Authors: Patal R, McIntosh L, McLaughlin J, Brooke S, Nimon V, and Sapolsky R ART
Yr: 2002 Vol: 82 Nbr: Abs: Pg: 118

HSV-mediated delivery of virally derived anti-apoptotic genes protects the rat hippocampus from damage following excitotoxicity but not metabolic disruption.
Periodical: Gene Therapy Index Medicus:
Authors: Roy M, Hom J, and Sapolsky R ART
Yr: 2002 Vol: 9 Nbr: Abs: Pg: 214