Gene Therapy Department - University of North Carolina at Chapel Hill
 
Research

     Samulski Lab
    Kafri Lab
    Monahan Lab
    McCown Lab

     Asokan Lab

Vector Core Facilities

    Services

     MJFF Request
    MTA
    Clinical Wing
    Research Wing

Clinical Trials
Administration
    Directors Offices
    Employment
    Contributions
Strategic Partners
    Asklepios
    MDA
    Duke University
    Robert Wood Johnson
    Ohio State University
    University of Pittsburgh
Gene Therapy Links
 
 

McCown Lab

Thomas McCownThomas McCown, PhD

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 epilepsy, 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. 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. Further studies showed that expression and constitutive secretion of galanin prevented both behavioral and electrographic limbic seizure activity elicited by peripheral administration of kainic acid. 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:

  • McCown TJ.Adeno-Associated Virus (AAV) Vectors in the CNS. Curr Gene Ther. 2011 Apr 1.PMID: 21453285
  • McCown TJ.The future of epilepsy treatment: focus on adeno-associated virus vector gene therapy. Drug News Perspect. 2010 Jun;23(5):281-6. Review.PMID: 20603651
  • McCown TJ.Adeno-associated virus vector-mediated expression and constitutive secretion of galanin suppresses limbic seizure activity.Neurotherapeutics. 2009 Apr;6(2):307-11. Review.PMID: 19332324
  • Papadeas ST, Halloran C, McCown TJ, Breese GR, Blake BL .Changes in apical dendritic structure correlate with sustained ERK1/2 phosphorylation in medial prefrontal cortex of a rat model of dopamine D1 receptor agonist sensitization. J Comp Neurol. 2008 Nov 10;511(2):271-85.PMID: 18785628
  • Foti S, Haberman RP, Samulski RJ, McCown TJ. Adeno-associated virus-mediated expression and constitutive secretion of NPY or NPY13-36 suppresses seizure activity in vivo. Gene Ther. 2007 Nov; 14 ( 21 ): 1534-6 . Epub 2007 Aug 23.
  • McCown TJ. Adeno-associated virus-mediated expression and constitutive secretion of galanin suppresses limbic seizure activity in vivo. Mol Ther. 2006 Jul; 14 ( 1 ): 63-8 . Epub 2006 May 30.
  • McCown TJ. Adeno-associated virus (AAV) vectors in the CNS. Curr Gene Ther. 2005 Jun; 5 ( 3 ): 333-8 . Review.
  • McCown TJ. The clinical potential of antiepileptic gene therapy. Expert Opin Biol Ther. 2004 Nov; 4 ( 11 ): 1771-6 . Review.
  • Haberman RP, Samulski RJ, McCown TJ. Attenuation of seizures and neuronal death by adeno-associated virus vector galanin expression and secretion. Nat Med. 2003 Aug; 9 ( 8 ): 1076-80 . Epub 2003 Jul 13.

 

Personnel

Marc Weinberg

 

 

 

 

 

UNC Gene Therapy Center Contact Information
Gene Therapy Center Home University of North Carolina at Chapel Hill Contact the Gene Therapy Center