Gene Therapy Protects Neurons From Stress Response

NEW YORK (Reuters Health) - In a rat model of brain injury, gene therapy to block the action of the glucocorticoid receptor in the neuronal stress-response pathway protects the neurons and reduces lesion size, researchers at Stanford University report.

After necrotic injuries from stroke, seizure or hypoglycemia, glucocorticoid secretion is increased, exacerbating steps in the reactive oxygen species cascade, Dr. Daniela Kaufer and her team explain. According to their report in Nature Neuroscience, published online August 8, their aim was to identify actions of glucocorticoids that represent targets for therapeutic intervention.

Toward that end, they designed three genetic interventions to block corticosterone-induced translocations of native glucocorticoid receptor (GR) expressed in rat neurons.

Using herpes simplex virus vectors, they introduced one gene that increased the rate of glucocorticoid breakdown, and another that encodes a modified GR that cannot bind ligands or initiate transcription. The third intervention created a chimeric receptor combining the ligand-binding domain of the GR and the DNA-binding domain of the estrogen receptor (ER), thus diverting the glucocorticoid signal into the protective estrogenic pathway.

In vitro, the vectors reduced the effects of corticosterone on neurons exposed to the neuron-specific excitotoxin kainic acid. Kainic acid reduced neuron survival, and preincubation with corticosterone exacerbated the toxicity, reducing neuronal survival from 37% to 21%. Each of the three genetic interventions prevented the neurons from the negative effects of corticosterone, but not of kainic acid itself.

To test the in vivo effect, Dr. Kaufer's team injected each vector into the dentate gyrus of the hippocampus in rats, along with kainic acid. When the lesion sizes were assessed 72 hours later, they found that "the fractional lesion volume was directly correlated with the distance from the site of vector injection."

The most effective intervention was the GR-ER chimera, which reduced the size of the lesion to 37% of that seen with a control vector. The other two vectors also significantly reduced lesion size by about 50%.

Such a strategy could be advantageous over adrenalectomy performed to block glucocorticoid secretion, the authors note, because it would block GR in the brain without affecting the more beneficial peripheral actions of glucocorticoids. The genetic intervention would also leave in place the protective effects of mineralocorticocoid receptor-mediated actions.

These findings highlight the potential of extrinsic endocrine modulators of neuron death, such as estrogen and brain-induced neurotrophic factor, as targets for therapy in the aging brain, co-author Dr. William O. Ogle told Reuters Health. "We hope to try these vectors to see how we can modify the stress response, and how that alters learning and memory."

Dr. Kaufer, Dr. Ogle and Dr. Z. S. Pincus are equal contributors to this work.

Source: Nat Neurosci 2004. [ Google search on this article ]

MeSH Headings: Biological Therapy : Genetic Engineering : Genetic Techniques : Heterocyclic Compounds : Heterocyclic Compounds, 1-Ring : Kainic Acid : Investigative Techniques : Pyrrolidines : Receptors, Estrogen : Receptors, Glucocorticoid : Receptors, Steroid : Therapeutics : Transcription Factors : Gene Therapy : Receptors, Cytoplasmic and Nuclear : Analytical, Diagnostic and Therapeutic Techniques and Equipment : Chemicals and Drugs

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