Epilepsy afflicts approximately 1% of the population, yet close to 30% of this population proves drug resistant, leaving surgical resection as the last treatment option (Hauser and Hesdoffer, 1990). Recently, Haberman et al. (2003) established a novel gene therapy platform where neuroactive peptides are expressed and constitutively secreted. These AAV vectors expressed and secreted enough galanin in vivo to significantly attenuate both focal and generalized limbic seizure activity. Furthermore, McCown (2006) recently showed that AAV vectors that expressed and secreted galanin could significantly attenuate, or even block, limbic seizure activity. However, two important issues must be addressed prior to any clinical consideration. In humans, any gene therapy will inevitably encounter both seizure-induced pathological tissue and pre-existing immunity to AAV serotype 2. The present proposal will first determine the most efficacious AAV vector configuration in a model of chronic seizure activity, focusing upon AAV serotype 5, self-complementary AAV and a human synapsin promoter. Secondly, as found by Peden et al. (2004), studies will confirm the ability of AAV serotype 5 vectors to evade immunity to AAV serotype 2 with a particular focus on anti-seizure efficacy. To further optimize the anti-seizure efficacy, studies will determine if the inclusion of a furin cleavage site supports the expression and secretion of two or more gene products from a single AAV vector, thus increasing the potential therapeutic applications of AAV vectors to CNS disorders. All together, these studies will provide information crucial for devising the most effective AAV vector antiepileptic gene therapy, as well as establish novel technological advances that will greatly benefit the entire gene therapy community. Epilepsy afflicts approximately 1% of the population, yet close to 30% of this population prove drug resistant, leaving surgical resection as the last treatment option. The present proposed studies will define the most efficacious adeno-associated virus vector which will provide a viable gene therapy treatment for intractable epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS035633-12
Application #
7738934
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Fureman, Brandy E
Project Start
1997-04-01
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
12
Fiscal Year
2010
Total Cost
$313,699
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Psychiatry
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Weinberg, Marc S; Blake, Bonita L; McCown, Thomas J (2013) Opposing actions of hippocampus TNF? receptors on limbic seizure susceptibility. Exp Neurol 247:429-37
Gray, S J; Nagabhushan Kalburgi, S; McCown, T J et al. (2013) Global CNS gene delivery and evasion of anti-AAV-neutralizing antibodies by intrathecal AAV administration in non-human primates. Gene Ther 20:450-9
Hayes, Dayna M; Fee, Jon R; McCown, Thomas J et al. (2012) Neuropeptide Y signaling modulates the expression of ethanol-induced behavioral sensitization in mice. Addict Biol 17:338-50
Weinberg, M S; Blake, B L; Samulski, R J et al. (2011) The influence of epileptic neuropathology and prior peripheral immunity on CNS transduction by rAAV2 and rAAV5. Gene Ther 18:961-8
Gray, Steven J; Foti, Stacey B; Schwartz, Joel W et al. (2011) Optimizing promoters for recombinant adeno-associated virus-mediated gene expression in the peripheral and central nervous system using self-complementary vectors. Hum Gene Ther 22:1143-53
McCown, Thomas J (2011) Adeno-Associated Virus (AAV) Vectors in the CNS. Curr Gene Ther 11:181-8
Johnson, Jarrod S; Li, Chengwen; DiPrimio, Nina et al. (2010) Mutagenesis of adeno-associated virus type 2 capsid protein VP1 uncovers new roles for basic amino acids in trafficking and cell-specific transduction. J Virol 84:8888-902
Koh, Ming Teng; Haberman, Rebecca P; Foti, Stacey et al. (2010) Treatment strategies targeting excess hippocampal activity benefit aged rats with cognitive impairment. Neuropsychopharmacology 35:1016-25
McCown, Thomas J (2010) The future of epilepsy treatment: focus on adeno-associated virus vector gene therapy. Drug News Perspect 23:281-6
McCown, Thomas J (2009) Adeno-associated virus vector-mediated expression and constitutive secretion of galanin suppresses limbic seizure activity. Neurotherapeutics 6:307-11

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