A better understanding of the causes of Prader-Willi syndrome (PWS) and the discovery of potential therapies has been hampered by the unavailability of live tissues. In our laboratory (Marc Lalande), we have established induced pluripotent stem cell (iPSC) technology to create models of human disease in a test tube/tissue culture dish. Skin cells obtained from patients can be programmed to become induced pluripotent stem cells (iPSCs) having two important properties. The first is that iPSCs can grow indefinitely in the tissue culture dish and the second is that iPSCs can potentially become any one of the 200 cell types in the human body. We propose to establish iPSCs from PWS skin cells. After testing the quality of the iPSCs, we will generate brain cells (neurons) from the iPSCs using special reagents and tissue culture conditions. Once we have established that our iPSC cell lines have the capacity to become neurons, we will try to alter the conditions in order to enrich for neurons of the hypothalamus, since this is a part of the brain that is probably affected in PWS. Our goal is to establish the best conditions for producing PWS neurons. Next, we will compare PWS neurons to neurons derived from iPSCs from unaffected individuals in order to identify genes that are abnormally controlled in PWS and to search for functional changes in the PWS neurons. Ultimately, we plan to establish a system whereby PWS neurons in tissue culture dishes can used in screening assays for compounds that restore normal gene expression patterns and, potentially, physiological function.
Marc Lalande, PhD
University of Connecticut Stem Cell Institute