Translational Advancement of Somatostatin Gene Delivery for Disease Modification and Cognitive Sparing in Intractable Epilepsy
Annual rept. 1 Sep 2013-31 Aug 2014
FLORIDA UNIV GAINESVILLE
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Roughly a third of epileptic patients cannot be satisfactorily treated by medication or surgery, and delayed development of epilepsy is a frequent outcome from brain trauma. Intracranial gene transfer could provide an alternative to surgical resection in pharmacologically resistant epilepsy, or where resection is not an option. This project tests whether somatostatin, delivered using a gene therapy approach, can modify epileptic phenotypes in a ratkindling model of epilepsy by modulating aberrant hippocampal neuron production and neuroinflammation. To date, we have replicated our finding that the delivery of a somatostatin gene to hippocampal neurons, using a vector based on adeno-associated virus, can reverse the most severe Class 5 seizure behavioral phenotype. We have generated strong preliminary evidence that the seizure kindling procedure strongly and selectively upregulates somatostatin type-2 receptor protein expression on hippocampal astrocytes. Kindling also strongly upregulates the production of new hippocampal dentate gyrus cells in these animals. We are currently quantifying these effects. We are generating the kindled seizure animals in which we can test the effects of somatostatin gene delivery on aberrant neurogenesis, neuroinflammation and learning and memory. The studies will establish improved understanding of therapeutic mechanisms, translational suitability, and appropriate outcome measures to advance toward more effective treatment ofepilepsy.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research
- Stress Physiology