The Use of Viral Vector Mediated Gene Delivery and Stem Cell Engineering in Gene-Based and Cell-Based Therapies.

My research employs molecular and cellular engineering approaches to investigate biomedical problems. We are interested in stem cell engineering, gene delivery systems, and molecular virology, with applications in gene-based and cell-based therapies and for gene discovery.

Areas of interest:

1. Neurodegenerative diseases

Gene and protein transfer in animal models of human neurodegenerative disorders. Major efforts of my lab deal with the delivery of therapeutic genes to cells in the CNS. Our goal is to develop improved gene and protein transfer strategies for the CNS. Toward this goal, we are testing the capacity of lentiviral vectors and of vectors based on adeno-associated virus (AAV) 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 (globoid cell leukodystrophy) which is a neurodegenerative disorder leading to demyelination and for which there is no cure.

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. Ongoing experiments involve improving the transduction efficiency and transgene expression of HIV-1-based lentiviral vectors bearing glycoproteins from rabies and rabies-related viruses in vitro, and optimizing their retrograde transport capacity in vivo. We next plan to compare the utility of constitutive and MN-specific promoters. Subsequent experiments will assess the therapeutic application of these strategies on the SMA mouse model by delivering genes encoding the survival motor neuron protein and insulin-like growth factor I, delivered peripherally with lentiviral vectors.

For the development of translational therapies for human diseases, comparative studies in animals other than mice would be advantageous. Recently, we have initiated a collaboration with investigators at the AudubonCenter for Research of Endangered Species in New Orleans to establish lentivirus-mediated transgenesis approaches in cats. Our long-term goal is to establish cat-based models of human neurodegenerative disorders.

2. Cancer

Mesenchymal stem cells to deliver therapeutic proteins to cancer cells in vivo. My lab is 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 ability of MSCs to home to vascularized tumors through genetic modification. We are also pursuing novel MSC-based strategies involving therapeutic peptides that selectively target leukemic cells in vivo.

3. Vectorology

Design of improved lentiviral vectors. My scientific interests during the past 11 years have focused on the design of novel vector systems for gene delivery into nondividing cells including quiescent hematopoietic stem cells and post-mitotic neurons. I was among the first to design lentiviral vectors based on HIV-1. Our paper (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) was one of the three original reports that emerged on the subject in 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 controlled and/or cell-specific production of therapeutic proteins and of small interfering RNAs both in vitro and in vivo. Another project focuses on novel strategies allowing targeted integration of lentiviral vectors. We plan to establish directed evolution approaches to engineer the properties of viral vectors at the molecular level to enhance their ability for transgene delivery and expression.

Link to Dr. Reiser's Faculty page