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Dr. Theodore Friedmann - Gene Therapy Lab

Dr. Theodore Friedmann

 Theodore Friedmann, A.B., M.D.

University of Pennsylvania and M.A., University of Oxford. Dr. Friedmann continues to study Lesch Nyhan Disease (LND), a neuro-developmental disease. His lab is concentrating on microarray and proteomic characterizations of human fibroblasts derived from LND patients, and of affected brain regions of the HPRT gene knockout mouse model.  Dr. Friedmann’s lab has identified a number of genes and gene families that are aberrantly expressed in LND, and is presently examining their potential role in the development of the disorder’s neuropathology. The lab is using microarray and proteomic approaches to characterize the molecular basis for the defect in the basal ganglia dopamine pathways by beginning to characterize the molecular events that accompany the differentiation of human embryonic stem cells toward the dopaminergic neuronal phenotype. Dr. Friedmann is continuing to study the assembly and gene transfer properties of synthetic virus-like nanoparticles (virosomes), and the molecular mechanisms of growth enhancement by the growth factor IGF-1 in cultured cells and in mice in vivo. In addition, he has continued an extensive series of studies in vitro and in vivo of the mechanism of action of insulin-like growth factor (IGF-1), using gene expression and proteomic approaches. As part of that research program, he has established a bioinformatic facility under the sponsorship of the World Anti-Doping Agency (WADA) that will coordinate the worldwide research program of growth factors and related functions under the auspices of WADA.


About the Lab

The Friedmann laboratory has long been interested in the development of the concepts and techniques of human gene therapy. These interests have taken the form of work in a variety of gene transfer vector systems, most notably the development of the VSV-G pseudotyping methods of retroviruses and more recently the development of self-assembled nanoparticles that enhance gene transfer of naked plasmids or liposomes through the incorporation of envelope protein receptor ligands such as VSV-G or other viral envelope glycoproteins. Previous disease models of interest have included neoplastic, cardiovascular and CNS disorders and now focus on Lesch Nyhan Disease, a neuro-developmental disorder caused by deficiency of the purine biosynthetic enzyme hypoxanthine guanine phosphoribosyltransferase (HPRT) and associated with disordered dopamine neurotransmission in the brain. We are approaching this complex monogenic disease by extensive characterization of the effects of HPRT gene mutations on global gene expression patterns and on the proteome of affected tissues. To understand how the brain development of the dopamine neurotransmitter system goes awry in HPRT deficiency, we are now applying these molecular methods to a study of normal and HPRT-deficient human embryonic stem cells as they differentiate into dopaminergic neurons.

We are also currently carrying out similar extensive studies of the effects of growth factors and anabolic steroids on gene expression and on the proteomes of muscle cells in culture and on mouse muscle and other tissues in vivo. These studies are aimed partly at developing molecular screening methods for gene-based doping in sport.

News & Research

Our current studies concentrate on the mechanisms of the dopamine deficit in Lesch Nyhan Disease and on identifying the possible defect in that disorder of differentiation of embryonic stem cells (ES) and neural stem cells to the dopaminergic phenotype. Toward that goal, we are examining the global patterns of gene expression and the proteomes of HPRT-deficient tissues and cells from the HPRT-knockout mouse model of Lesch Nyhan Disease (LND), and we have identified a number of candidate genes whose expression seems to be correlated with the in vitro differentiation of the parent ES cells toward the dopaminergic neuron phenotype. We wish to use these methods to identify the mechanisms underlying the presumed aberrant dopaminergic development in LND and to use this knowledge to design methods for producing dopaminergic neurons in vitro from embryonic stem cells and from neural stem cells. We are continuing our biochemical and functional studies of these genes and their role in the HPRT-deficiency neurological phenotype, and in particular the possibility of aberrant electron transport and mitochondrial dysfunction in the HPRT knockout mouse model of LND. Our laboratory is also pursuing extensive studies on the effects of insulin-like growth factor (IGF-1) and several other growth factors on global gene expression and on the proteomes of cultured myoblasts and on tissues in mice treated with growth factors. We have identified very complex interactions among several gene families that respond to in vivo exposure to IGF-1 and are carrying out genetic and biochemical studies to We are continuing our studies examining the in vitro assembly of virus-like nanoparticles and virosomes in an effort to produce efficient and targeted non-viral gene transfer methods.