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:

• Weinberg MS, Blake BL, Samulski RJ, McCown TJ, The influence of epileptic neuropathology and prior peripheral immunity on CNS transduction by rAAV2 and rAAV5. Gene Ther. 2011, Apr 14. PMID: 21490684

• Gray SJ, Foti SB, Schwartz JW, Bachaboina L, Taylor-Blake B, Coleman J, Ehlers MD, Zylka MJ, McCown TJ, Samulski RJ. Optimizing promoters for rAAV-mediated gene expression in the peripheral and central nervous system using self-complementary vectors. Hum Gene Ther. 2011 Apr 8. PMID: 21476867

• McCown TJ.Adeno-Associated Virus (AAV) Vectors in the CNS. Curr Gene Ther. 2011 Apr 1.PMID: 21453285

• Kantor B, Bayer M, Ma H, Samulski J, Li C, McCown T, Kafri T. Notable reduction in illegitimate integration mediated by a PPT-deleted, nonintegrating lentiviral vector. Mol Ther. 2011 Mar;19(3):547-56. Epub 2010 Dec 14.PMID: 21157436

• 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

• Johnson JS, Li C, DiPrimio N, Weinberg MS, McCown TJ, Samulski RJ. 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. 2010 Sep;84(17):8888-902. Epub 2010 Jun 23.PMID: 20573820

• Gray SJ, Blake BL, Criswell HE, Nicolson SC, Samulski RJ, McCown TJ, Li W. Directed evolution of a novel adeno-associated virus (AAV) vector that crosses the seizure-compromised blood-brain barrier (BBB). Mol Ther. 2010 Mar;18(3):570-8. Epub 2009 Dec 29. Erratum in: Mol Ther. 2010 May;18(5):1054. Li, Wuping [added]. PMID: 20040913

• Koh MT, Haberman RP, Foti S, McCown TJ, Gallagher M.Treatment strategies targeting excess hippocampal activity benefit aged rats with cognitive impairment.Neuropsychopharmacology. 2010 Mar;35(4):1016-25. Epub 2009 Dec 23.PMID: 20032967

• 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

• Li 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.

• 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.

• Choi VW, Asokan A, Haberman RA, McCown TJ, Samulski RJ. Production of recombinant adeno-associated viral vectors and use for in vitro and in vivo administration. Curr Protoc Neurosci. 2006 May; Chapter 4 : Unit 4.17 .

• 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.

• Cockrell AS, Ma H, Fu K, McCown TJ, Kafri T. A trans-lentiviral packaging cell line for high-titer conditional self-inactivating HIV-1 vectors. Mol Ther. 2006 Aug; 14 ( 2 ): 276-84 . Epub 2006 Mar 3.

• 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.

• Haack K, Cockrell AS, Ma H, Israeli D, Ho SN, McCown TJ, Kafri T. Transactivator and structurally optimized inducible lentiviral vectors. Mol Ther. 2004 Sep; 10 ( 3 ): 585-96 .

• 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.

• Haberman, 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.

 

Personnel

Marc Weinberg