School of Medical Sciences

Gene therapy

Principal investigator


  • Jerusha Naidoo
  • Thomas Chen
  • Tatyana Wagner
  • Jerry Wong


  • Dr Trish Lawlor
  • Dr Sasha Muravlev
  • Dr Dahna Fong
  • Joelene Qiao
  • Ernest Sirimanne
  • Janitha Mudannayake


  • Andrew Brooks, University of Rochester
  • Carlo Croce, Ohio State University
  • Mike Dragunow, Department of Pharmacology
  • Todd Golde, Mayo Clinic
  • Maggie Kalev, Department of Molecular Medicine and Pathology
  • Janusz Lipski, Department of Physiology
  • Michael Kaplitt, Cornell University  
  • Richard Palmiter, University of Washington
  • Russell Snell, Vialactia Biosciences


Our research interests are broad and range from the study of the molecular basis of learning and memory, to gene therapy of neurological disorders. The main common theme is the use of somatic cell gene transfer to study neuronal physiology and to treat human disease.

Our research covers the full spectrum from molecular biology through to animal behaviour and human clinical trials. For our gene therapy program, in the first instance "proof of principle" experiments are conducted to test therapeutic concepts in an attempt to obtain phenotypic correction in models of neurological disease.

Promising approaches are advanced to human clinical trials. Many of our research projects involve collaborations and our laboratory is of international standing and forms a key role in a major network of mammalian brain gene interventionists. Our gene therapy group is an international collaborative group of investigators at Auckland and Ohio.

Research projects

Vectorology program

Our vectorology program is primarily orientated around adeno-associated virus (AAV) as a vector gene delivery system. Our efforts are focused on improvements in these systems including increased efficiency of gene transfer/transduction; stable and regulated transgene expression; gene silencing; vector targeting; and decreased toxicity/pathogenicity of the vector systems as well as development of animal models of neurological disease, including Parkinson's, Huntington's and Alzheimer's Disease.


Parkinson's Disease

We have an extensive Parkinson's Disease research program, ranging from generating novel genetic models of Parkinson's Disease, investigation of mechanisms underlying Parkinson's neuropathology, as well as the development of therapeutic strategies. Early work focused on dopamine replacement and growth factor strategies. More recently, we have developed a strategy to reset brain circuitry altered in Parkinson's. Following promising preclinical studies, we have obtained FDA approval for the world's first human Phase I clinical trial using a gene therapy approach for Parkinson's Disease.


Alzheimer's Disease/Huntington's Disease

New research directions for our lab include developing genetic models of Huntington's and Alzheimer's Diseases and the development of therapeutic strategies for these diseases.


Learning and memory

We have a long-standing interest in the molecular mechanisms of learning and memory. Our current approach is focused on altering candidate molecular gene expression (signal transduction enzymes and transcription factors) in specific brain regions using viral vectors and defining alterations in brain neurochemistry and physiology which mediate phenotypic effects on learning and memory.



Our laboratory has a long-standing interest in the use of microdialysis in the conscious human brain. Our major efforts have been to determine the mechanisms underlying epilepsy specifically focusing on the GABergic and glutamatergic transmitter systems. In addition we have looked at effects of novel antiepileptic drugs (AEDs) on brain chemistry to define mechanisms of action as well as the use of AEDs as probes to look at receptor and transporter changes in the human epileptic brain. We are currently developing approaches for gene therapy of the epilepsies.


Vaccines for neurological disease

We are characterising genetic and protein vaccine approaches as potential prophylactic approaches for stroke and epilepsy.


Effects of environment on brain structure and function

We have an interest in the effects of environment on brain structure and function. We and others have found that complex social and physical stimulation increases new cell birth within the hippocampus. This process called neurogenesis has implications for learning and memory as well as neurological disease.


Recent research publications

  1. Lawlor PA, Bland RJ, Mouravlev A, Young D, During MJ (2009) Efficient gene delivery and selective transduction of glial cells in the mammalian brain by AAV serotypes isolated from non-human primates. Mol. Ther.17(10):1692-702.
  2. Kalev-Zylinska ML, Symes W, Young D, During MJ (2009) Knockdown and overexpression of NR1 modulates NMDA receptor function. Mol Cell Neurosci. 41(4):383-96.
  3. Franich NR, Fitzsimons HL, Fong DM, Klugmann M, During MJ, Young D (2008) AAV vector-mediated RNAi of mutant huntingtin expression is neuroprotective in a novel genetic rat model of Huntington's disease.. Mol. Ther. 16:947-956.
  4. Jung AE, Fitzsimons HL, Fong DM, Bland RJ, During MJ, Young D. (2008) HSP70 and constitutively active HSF1 mediate protection against CDCrel-1-mediated toxicity. Mol Ther 16:1048-55
  5. Kaplitt, M.G., Feiglin, a., Tang, C., Fitzsimons, H.L., Mattis, P., Lawlor, P.A., Bland, R.j., Young, D., Strybing, K., Eidelberg, D., and During, M.J. (2007) Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson's disease: an open label, phase I trial.  Lancet 369, 2097-2105.
  6. Emborg, M.E., Carbon, M., Holden, J.E., During, M.J., Ma, Y., Tang, C., Moirano, J., Fitzsimons, H., Roitberg, B.Z., Tuccar, E., Roberts, A., Kaplitt, M.G., and Eidelberg, D. (2007). Subthalamic glutamic acid decarboxylase gene therapy: changes in motor function and cortical metabolism.  J Cereb Blood Flow Metab 27, 501-509.
  7. Feigin, A., Kaplitt, M.G., Tang, C., Lin, T., Mattis, P., Dhawan, V., During, M.J. and Eidelberg, D. (2007). Modulation of metabolic brain networks after subthalamic gene therapy for Parkinson's disease.  Proc Natl Acad Sci USA 104, 19559-19564.
  8. Kalev-Zylinska, M.L. and During, M.J. (2007) Paradoxical facilitatory effect of low-dose alcohol consumption on memory mediated by NMDA receptors. J Neurosci 27, 10456-10467.
  9. Lawlor, P.A., Bland, R.J., Das, P., Price, R.W., Holloway, V., Smithson, L., Dicker, B.L., During, M.J., Young, D. and Golde, T.E. (2007) NOvel rat Alzheimer's disease models based on AAV-mediated gene transfer to selectively increase hippocampal Abeta levels.  Mol Nurodegener 2, 11.
  10. Mouravlev, A., Young, D. and During, M.J. (2007) Phophorylation-dependent degradation of transgenic CREB protein initiated by heterodimerization.  Brain Res 1130, 31-37.
  11. Mouravlev, A., Dunning, J., Young, D., and During, M.J. (2006) Somatic gene transfer of cAMP response element-binding protein attenuates memory impairment in aging rats. Prot Natl Acad Sci USA 103, 4705-4710.
  12. Klugmann, M., Leichtlein, C.B., Symes, C.W., Klaussner, B.C., Brooks, A.I., Young, D. and During, M.J.(2006) A novel role of circadian transcription facter DBP in hippocampal plasticity. Mol CellNeurosci 31, 303-314.
  13. Lin, E.J., Young, D., Baer, K., Herzog, H. and During, M.J. (2006) Differential actions of NPY on seizure modulation via Y1 and Y2 receptors: evidence from receptor knockout mice. Epilepsia 47, 773-780.
  14. Klugmann, M., Leichtlein, C.B., Symes, C.W., Serikawa, T., Young, D. and During, M.J. (2005) Restoration of aspartoacylase activity in CNS neurons does not ameliorate motor deficits and demyelination in a model of Canavan disease. Mol Ther 11, 745-753.
  15. Klugmann M, Wymond, S.C., Leichtlein C.B., Klaussner B.K., Dunning J, Fong D, Young D, During M.J., (2005) AAV-mediated hippocampal expression of short and long Homer 1 proteins differentially affect cognition and seizure activity in adult rats. Mol Cell Neurosci. 28:347-60.
  16. Cao L, Jiao X, Zuzga, DS, Liu, Y, Fong, D.M., Young D, During, M.J., (2004) VEGF links hippocampal activity with neurogenesis, learning and memory. Nature Genetics 36: 827-35.
  17. During MJ, Young D, Baer K, Lawlor P, Klugmann M.(2003)Development and optimization of adeno-associated virus vector transfer into the central nervous system. Methods Mol Med. 76:221-36.
  18. Luo J, Kaplitt MG, Fitzsimons HL, Zuzga DS, Liu Y, Oshinsky ML, During MJ. (2002) Subthalamic GAD gene therapy in a Parkinson's disease rat model. Science. 298(5592):425-9.
  19. Mastakov MY, Baer K, Symes CW, Leichtlein CB, Kotin RM, During MJ. (2002) Immunological aspects of recombinant adeno-associated virus delivery to the mammalian brain. J Virol. 76(16):8446-54.
  20. Janson CG, During MJ. (2001) Viral vectors as part of an integrated functional genomics program. Genomics. 78(1-2):3-6.
  21. During MJ, Kaplitt MG, Stern MB, Eidelberg D. (2001) Subthalamic GAD gene transfer in Parkinson disease patients who are candidates for deep brain stimulation. Hum Gene Ther. 12(12):1589-91.
  22. During, M.J., Symes, C.W., Lawlor, P.A., Lin, E-J., Dunning, J., Fitzsimons, H.L., Poulsen, D., Leone, P., Xu, R., DIcker, B.L., Lipski, J., Young, D. (2000). BM oral vaccine against NMDAR1 with efficacy in experimental stroke and epilepsy. Science 287:1453-1460.
  23. Telfeian, A.E., Federoff, H.J., Leone, P., During, M.J., Williamson, A.W. (2000) Overexpression of GluR-6 in rat hippocampi produces seizures and spontaneous nonsynaptic bursting in vitro. Neurobiol Dis 7(4):362-74.
  24. Young, D., Lawlor, P., Dragunow, M., During, M.J. (1999). Environmental enrichment inhibits spontaneous apoptosis, prevents seizures and is neuroprotective. Nature Medicine 5:445-453.
  25. During, M.J., Xu, R., Young, D., Kaplitt, M.G., Sherwin, R.S. and Leone, P. (1998) Peroral gene therapy of lactose intolerance using an AAV vector. Nature Medicine, 4, 1131-1135.