Gene Therapy - Wei-Ming Duan, M.D., Ph.D.

Key Member

Wei-Ming Duan, M.D., Ph.D.
Dept. of Cellular Biology and Anatomy

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Duan Office

The research of my laboratory focuses on the development of gene therapy and cell replacement therapy with stem cells for neurodegenerative disorders, especially for Parkinson's disease (PD). Specifically, we are working on an ex vitro approach to deliver a therapeutic gene of glial cell line-derived neurotrophic factor (GDNF) in an animal model of PD. GDNF has proven to be a potent neurotrophic factor for protection of nigral dopamine neurons against toxin-induced degeneration in vitro and in vivo. We are using lentiviral vectors to transduce either neural progenitor cells or bone marrow derived stem cells, and introducing them to an animal model of Parkinson's disease. Replication-defective lentiviral vectors is a powerful and promising tool in gene delivery system. Lentiviral vectors can infect both dividing and non-dividing cells in vitro and in vivo and do not encode viral proteins that may elicit an immune response. Stem cells represent a homogeneous source of cells for genetic, developmental, and gene transfer and repair studies in the brain. Stable self-renewing, multipotent, clonal stem cell lines are readily genetically modified ex vivo by standard retroviral techniques and can stably express transgenes robustly in vivo following transplantation. For gene therapy, one of the major challenges for the clinical application remains the necessity of gene regulation in order to achieve the expected therapeutic outcome while avoiding potential limiting side effects related to the over-expression of the transgene. In our studies, we are also working on generating an inducible gene delivery system with tetracycline (Tet)-regulated lentiviral vectors and stem cells. We will determine whether grafted stem cells that are genetically engineered to express GDNF will elicit cellular and behavioral recovery in parkinsonian rats and GDNF transgene can be regulated. We expect that these cells can migrate from the injection site to large areas of the brain and the levels of the transgene expression can be regulated along with therapeutic purposes. The big advantages of delivering transgenes by stem cells are that no genetic modification is introduced in the cells of the host and no viral particles have to be introduced in the brain. In addition, stem cells have been shown to participate in the repair of experimental CNS disorders. We anticipate that this approach may yield a better transgene delivery and open a possible route for clinical trials for gene therapies in treating PD, as well as other diseases of the central nervous system.

Another research line of my laboratory is to examine signal regulation of stem cell differentiation and connectivity, especially for adult stem cells. There are several big advantages and great clinical potentials to use adult stem cells because the use of adult stem cells enables to do autologous transplantation and can avoid immune responses. We will either induce neural stem cells or bone marrow derived stem cells to differentiate into a dopamine neuron population with a combination of growth factors in vitro and then implant them into an animal model of PD, or induce endogenous neural stem cells in the brain to differentiate into dopamine neurons and migrate into dopamine depleted areas in the brain. To accomplish experimental objectives, a combination of molecular and protein analysis, real-time PCR, siRNA technique and DNA microarray gene analysis will be used in the experiments. By increasing our understanding of the signals required for neuronal differentiation of stem cells, this study will provide a rationale for clinical cell replacement strategies for the treatment of various neurodegenerative disorders and traumatic injuries where neuron loss takes place.

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