Thomas McCown, PhD
Professor of Psychiatry
PhD, Vanderbilt University
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.
- 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
W, Asokan A, Wu Z, Van Dyke T, DiPrimio N, Johnson JS,
Govindaswamy L, Agbandje-McKenna M, Leichtle S, Redmond
DE Jr, McCown TJ, Petermann KB, Sharpless NE, Samulski
RJ. Engineering and selection of shuffled AAV
genomes: a new strategy for producing targeted biological
nanoparticles. Mol Ther. 2008 Jul; 16 ( 7 ): 1252-60 .
Epub 2008 May 20.
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.
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.
TJ. Adeno-associated virus (AAV) vectors in
the CNS. Curr Gene Ther. 2005 Jun; 5 ( 3 ): 333-8 . Review.
TJ. The clinical potential of antiepileptic
gene therapy. Expert Opin Biol Ther. 2004 Nov; 4 ( 11
): 1771-6 . Review.
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.
R.P., Criswell, H.E., Snowdy, S., Ming, Z., Breese, G.R.,
Samulski, R.J. and McCown, T.J. Therapeutic liabilities
of in vivo viral vector tropism: adeno-associated
virus (AAV) Vectors, NMDAR 1 antisense and focal seizure
sensitivity . Mol Ther 6:495-500,2002.