Design of lentiviral vectors. Our scientific interests during the past 10 years have focused on the design of novel vector systems for gene delivery into nondividing cells including post-mitotic neurons. We were among the first to design lentiviral vectors based on HIV-1 (Reiser et al. Transduction of nondividing cells using pseudotyped defective high-titer HIV type 1 particles, Proc. Natl. Acad. Sci. USA 93, 15266-15271, 1996). We have subsequently made a number of improvements that are relevant to the safety, flexibility and efficiency of lentiviral vectors. Ongoing efforts in the lab focus on the design of tightly regulatable lentiviral vectors allowing temporarily and spatially controlled production of therapeutic proteins and of small interfering RNAs both in vitro and in vivo.



Gene and protein transfer to cells in the central nervous system. Other efforts in the lab deal with improved gene and protein transfer strategies for the CNS. Toward this goal, we are testing the capacity of various lentiviral vector pseudotypes delivered locally or systemically to transduce cells located in the CNS. Therapeutic effects of this approach are being assessed in the twitcher mouse model of Krabbe disease which is a neurodegenerative disorder leading to demyelination and for which there is no cure.


In a collaborative effort with investigators at the Cleveland Clinic, we are developing improved strategies for delivery and cell-specific expression of transgenes in CNS motor neurons (MNs), via retrograde transport and using cell-specific promoters. We have elected to focus on spinal muscular atrophy (SMA) because this MN disease results from mutation of an identified gene, lending this disorder to the clinical translation of a gene therapy approach. Moreover, because SMA therapies are most likely to be administered initially to type III SMA patients, we will utilize a new mouse model for type III disease.



Genetic modification of mesenchymal stem cells. Our lab is also engaged in work aimed at using mesenchymal stem cells (MSCs) in tissue repair strategies and cancer. We were the first to use lentiviral vectors to genetically modify such cells (Zhang et al. Lentiviral vectors for sustained transgene expression in human bone marrow-derived stromal cells, Molecular Therapy 5, 555-556, 2002). Our goal is to improve the tissue engraftment and tumor-homing ability of MSCs through genetic modification.



Lentivirus-mediated transgenesis in cats. Recently, we have initiated a collaboration with investigators at the Audubon Center for Research of Endangered Species in New Orleans to establish lentivirus-mediated transgenesis approaches in domestic cats. Our long term goal is to establish cat-based models of human neurodegenerative disorders.