Professor of Psychiatry

PhD, Vanderbilt University

Phone: 919.966.3081

thomas_mccown@med.unc.edu

Many neurological disorders provide attractive targets for gene therapy, especially given the predominant neural tropism exhibited by adeno-associated virus (AAV) vectors. In order to attain effective therapies, however, broad gene therapy principles must be tailored to each individual disorder. One particularly attractive target, focal epilpsy, comprises the major research focus of my laboratory. Initially, we targeted excitatory amino acid receptors with an AAV antisense approach, but unexpectedly found that slight changes in the promoter produced diametrically opposed results. In one instance focal seizure sensitivity decreased while in the other instance the focal seizure sensitivity increased. Thus, slight differences in the population of transduced neurons created an unacceptable therapeutic liability for this strategy. Recently, we have circumvented this problem by developing a new approach to CNS gene therapy. As described in our Nature Medicine publication, we combined a fibronectin secretory sequence with the coding sequence for the neuroactive peptide, galanin, resulting in the expression and constitutive secretion of an active gene product. This approach attenuated seizure activity and prevented seizure-induced cell death in vivo, independent from the pattern of transduction. Current studies continue to explore the applicability to this gene therapy technique to the treatment of intractable focal epilepsies, as well as probe the potential for treating neurodegenerative disorders. Concomitant with these studies is the continuing effort to further define the basic mechanisms that determine AAV transduction in the CNS.

Publications:

• Haberman RP, Samulski RJ, McCown TJ. 2003. Attenuation of seizures and neuronal death by adeno-associated virus (AAV) vector galanin expression and secretion. Nature Medicine, 9(8):1076-80.
  
  
• Haberman RP, Criswell HE, Snowdy S, Ming Z, Breese GR, Samulski RJ, McCown TJ. 2002. Therapeutic liabilities of in vivo viral vector tropism: adeno-associated virus (AAV) vectors, NMDAR 1 antisense and focal seizure sensitivity. Molecular Therapy, 6(4):495-500.
  
  
• Haberman RP, McCown TJ, Samulski RJ. 2000. Novel transcriptional regulatory signals in the adeno-associated virus terminal repeat A/D junction element. Journal of Virology, 74(18):8732-8739.
  
  
• Bartlett JS, Samulski RJ, McCown TJ. 1998. Selective and rapid uptake of adeno-associated virus type 2 in brain. Human Gene Therapy, 9(8):1181-1186.
  
  
• Haberman RP, McCown TJ, Samulski RJ. 1998. Inducible long-term gene expression in brain with adeno-associated virus gene transfer. Gene Therapy, 5(12):1604-11.
  
  
• Xiao X, McCown TJ, Li J, Breese GR, Morrow AL, Samulski RJ. 1997. Adeno-associated virus (AAV) vector antisense gene transfer in vivo decreases GABA(A) alpha1 containing receptors and increases inferior collicular seizure sensitivity. Brain Research, 756(1-2):76-83.
  
  
• McCown TJ, Xiao X, Li J, Breese GR, Samulski RJ. 1996. Differential and persistent expression patterns of CNS gene transfer by an adeno-associated virus (AAV) vector. Brain Research, 713(1-2):99-107.
  
  
• McCown TJ, Duncan GE, Johnson KB, Breese GR. 1995. Metabolic and functional mapping of the neural network subserving inferior collicular seizure generalization. Brain Research, 701(1-2):117-128.
  
  
• McCown TJ, and Breese GR. 1992. The developmental profile of seizure genesis in the inferior collicular cortex of the rat: relevance to human neonatal seizures. Epilepsia, 33(1):2-10.
  

Personnel

Stacey Foti