Animal homologs of human genetic diseases are used as test systems for gene transfer by viral vectors. The approaches for transferring genes to the brain currently being investigated are ex vivo gene transfer using retrovirus and lentivius vector-modified neural stem cells transplanted to the brain and direct injection of herpesvirus, adeno-associated virus, and lentivirus vectors. The studies involve comparisons of promoters, properties of transduction for different cell types and various subregions of the brain. Studies are done on adult, neonatal and fetal animals. New methods to follow cell fate and gene expression in the live animal are being explored using MRI and PET techniques. Studies are also being directed towards better understanding of the mechanism of disease in the brain.

Vite, C.H., Niogi, S.N., McGowan, J.C., Passini, M.A., Drobatz, K.J., Haskins, M.E. and Wolfe, J.H. (2005) Effective gene therapy for an inherited diffuse CNS disease in a large animal model. Ann. Neurol., 57:355-36.

Magnitsky, S., Watson, D.J., Walton, R.M., Pickup, S., Bulte, J.M.W., Wolfe, J.H. and Poptani, H. (2005) MRI distinguishes between localized and disseminated neural stem cell grafts in the mouse brain. NeuroImage, 26:744-754.

Wolfe, J.H. , Acton, P., Poptani H. and Vite, C.H. (2005) Molecular imaging of gene therapy in neuro-genetic diseases. In: Gene Therapy in the Brain, Ed M.G. Kaplitt and M. During. Elsevier, Amsterdam, The Netherlands. In press.

Watson,D.J., Longhi, L., Lee, E.B., Fulp, C.T., Fujimoto, S., Royo , N.C. , Passini, M.A., Trojanowski, J.Q., Lee, V.M.-Y., McIntosh, T.K. and Wolfe, J.H. (2003) Genetically modified NT2N human neuronal cells mediate long-term gene expression as CNS grafts in vivo and improve functional cognitive outcome following experimental traumatic brain injury. J. Neuropath. Exp. Neurol., 62: 368-380.

Passini, M.A., Watson, D.J., Vite, C.H., Landsburg, D.J., Feigenbaum, A.L. and Wolfe, J.H. (2003) Intraventricular injection of AAV1 in neonatal mice results in complementary patterns of neuronal transduction to AAV2 and total long-term correction of storage lesions in the brains of ß-glucuronidase-deficient mice. J. Virol., 77: 7034-7040.

Vite, C.M., Passini, M., Haskins , M.E. and Wolfe, J.H. (2003) Adeno-associated virus vector-mediated transduction in the cat brain. Gene Ther., 10: 1874-1881.

Passini, M.A., Lee, E.B., Heuer, G.G. and Wolfe, J.H. (2002). Distribution of a lysosomal enzyme in the adult brain by axonal transport and by cells of the rostral migratory stream. J. Neurosci., 22: 6437-6446.

Heuer, G.G., Passini, M.A., Jiang, K., Parente, M.K., Lee, V.M.-Y., Trojanowski, J.Q. and Wolfe, J.H. (2002) Selective neurodegeneration in the murine mucopolysaccharidosis VII is progressive and reversible. Ann. Neurol., 52: 762-770.

Graduate Students

Cassia Cearley (Neuroscience, PhD), AAV vector topism in selected brain systems.
Carlos Gay-Antaki (Biochem Mol Biophys, PhD), Axonal transport of lysosomal enzymes in neurons.
Kelvin Tsang (Bioengineering, MS), Development of lentivirus vectors for increased enzyme secretion.

Postdocs and Fellowships

Brian Karolewski, VMD, In utero gene therapy in the CNS.
Tupur Husain, PhD, Increased gene expression in the CNS from AAV vectors.
Tyler Pierson, MD, PhD, Expanding neural stem cell migration for improved engraftment.
Raquel Walton, VMD, Differentiation and transplantation of canine neural stem cells.