Penn Veterinary Medicine | University of Pennsylvania

Description of Research Expertise

Research Interests
gene transfer in the central nervous system, genetic diseases, animal models, mechanisms of pathology.

Key words: gene therapy, viral vectors, brain, pathogenesis, lysosomal enzymes, neural stem cells, MRI and PET imaging, animal models, genetic diseases.

Description of Research
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. 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.

Rotation Projects for 2009-2010
Rotation projects are related to the molecular design and engineering of vectors, understanding the fate of vector-transferred genes in the brain, the regulation of foreign gene expression from vectors, neural stem cell biology,induced pluripotent stem cells (iPS), imaging studies, and proteomics and genomics analysis of neurodegenerative lesions. Projects can be tailored to the interest and experience of the student.

Selected Publications

Snyder, E.Y., Taylor, R.M. and Wolfe, J.H.: Neural progenitor cell engraftment corrects lysosomal storage throughout the MPS VII mouse brain. Nature 374: 367-370 Page: 367-370, 1995.

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

Passini, M.A., Lee, E.B., Heuer, G.G. and Wolfe, J.H.: Distribution of a lysosomal enzyme in the adult brain by axonal transport and by cells of the rostral migratory stream. J. Neurosci. 22: 6437-46 2002.

Vite, C.H., Niogi, S.N., McGowan, J.C., Passini, M.A., Drobatz, K.J., Haskins, M.E. and Wolfe, J.H. : Effective gene therapy for an inherited diffuse CNS disease in a large animal model. Ann. Neurol., 57: 355-364 2005.

Walton, R.M. and Wolfe, J.H.: Abnormalities in neural progenitor cells in a dog model of lysosomal storage disease. J. Neuropath. Exp. Neurol. 66: 760-769 2007.

Cearley, C.N. and Wolfe, J.H. : A single injection of an AAV vector into nuclei with divergent connections results in widespread vector distribution and global correction of a neurogenetic disease. J. Neurosci. 27: 9928-9940 2007.

Walton R.M., Magnitsky, S.G., Seiler, G.S., Poptani H., and Wolfe J.H. : Transplantation and magnetic resonance imaging of canine neural progenitor cell grafts in the postnatal dog brain. J. Neuropath. Exp. Neurol. Page: 954-962, 2008.

Cearley, C.N., Vandenberghe, L.H., Carnish, E.R., Parente, M.K., Wilson, J.M. and Wolfe, J.H.: Expanded repertoire of AAV vector serotypes mediate unique patterns of transduction in mouse brain. Mol. Ther. 16: 1710-1718, 2008.

Husain, T., Passini, M.A., Parente, M.K., Fraser, N.W. and Wolfe, J.H. (2009) : Long-term AAV vector gene and protein expression in mouse brain from a small pan-cellular promoter is similar to neural cell promoters. Gene Ther. 16: 927-932, 2009.

Wolfe, J.H. : Gene therapy in large animal models of human genetic diseases. Inst. Lab. Anim. Res. J. 50: 107-111, 2009.