January 22, 2015
We are excited to have this opportunity to discuss our research directions and plans for Mowat-Wilson Syndrome (MWS). Our research efforts are focused on a better fundamental understanding of MWS, at the cellular level, and to identify the specific molecular defects that cause this disorder to test treatment options.
The important work of Dr. Goosens in 2001 demonstrated that the underlying genetic basis of MWS is due to an alteration in a single gene named ZEB2. These findings have given us hope in defining MWS at the most fundamental level. However, knowing the underlying cause of a syndrome is only a beginning, and connecting this information with a better understanding of a disease is critical for identifying potential treatment plans and options.
Unfortunately, many research models attempting to mimic the various clinical symptoms of MWS have been largely unsuccessful. We are met with a similar challenge when studying many other developmental disorders: how do we study MWS at the most fundamental level when it is not possible to study the most relevant living cells from that patient, the neurons of the brain and other organs?
Our efforts are attempting to address these questions by using an exciting new method of ‘pluripotent cell reprogramming’, which we would like to briefly describe. In our work, we obtain cells from biopsies or tissue from surgical procedures from individuals with MWS and culture the cells in specially prepared tissue flasks under laboratory conditions. Tissue samples from biopsies or surgical procedures are taken only with the permission of the parents and assistance from the child’s physician and are quite small. They do not adversely affect the individual patient. Thus far we have been able to obtain cells from several different types of biopsies, including a small bit of tissue from the skin. We have also been successful in obtaining cells from stomach and colon biopsies. As you know, many individuals with MWS undergo gastrointestinal procedures which are straightforward and not stressful to have a physician take a biopsy from these organs when they are performing procedures.
Once we have these cells growing in a flask or dish in our laboratory, we then can convert or manipulate these cells to grow into another cell type called ‘pluripotent cells’. We then direct these pluripotent cells to turn into cells that we believe are relevant for studying the various symptoms seen in MWS. Our recent work has focused on developing methods to efficiently turn these patient cells growing in a dish into neuron cells, which we believe are the relevant cell type to study for MWS. We have recently developed a stepwise procedure to coax pluripotent cells efficiently into nerve cells.
One of the main questions we want to ask is, “What other genes are affected in MWS cells?” Our labs have been successful in uncovering similar ‘molecular signatures’ characteristic of many other developmental syndromes. Once the cells are converted to neurons, we can readily study them with a variety of methods. One of the methods we are most excited about is using these cells to perform small molecule or drug screens. The cells will be grown in the presence of drugs or medications to identify possible chemicals that may influence these molecular signatures with the hope to “fix” the molecular problems causing MWS.
Our efforts in using these technologies for MWS are just getting underway. We have been successful in obtaining biopsies from four different individuals with MWS, and we will begin the process of converting these cells to pluripotent cells this spring once additional funds are identified to undertake this process.
It may take time before we can answer many of these questions, but having these cells in our laboratory, now, allows us to move forward in a variety of important directions. We hope that by getting these cells in our lab, we can obtain funding to support this work.
We are extremely grateful to the MWS families for allowing their children to participate in these studies, and talking with their doctors to obtain these biopsies. Family participation is essential for this work to proceed, and the support has been overwhelming. We would also like to thank Deby Curry of the Mowat-Wilson Syndrome Foundation. She has been a critical part of connecting us with the families and doctors treating the children and adults with MWS. Finally we would like to thank the Mowat-Wilson Syndrome Foundation and the MWS families for providing us with the initial funds to begin this project. We are excited about these studies and using our discoveries to identify treatments for patients with MWS in the future.