Gustavo H.B. Maegawa, MD, PhD
Johns Hopkins School of Medicine, Department of Pediatrics
“Induced-neuronal (iN) cells as tools to study the pathogenesis of neurological manifestations in MPS-II.”
Mucopolysaccharidosis type II (MPS-II), or mostly known as Hunter syndrome, is a genetic disease caused by the inability to breakdown large molecules called glycosaminoglycans. MPSII is caused by the deficiency of an enzyme located in the lysosome, essential recycling units present in each cell. In MPS-II, the accumulation of undegraded material results in dysfunction of the lysosomes, compromising the entire cells and ultimately multiple organs/systems. The mechanisms how the storage of glycosaminoglycans can severely affect the brain cells causing severe mental disabilities are still not fully elucidated. Through this project funded by MPS Society, we established several types of brain cells directly from several MPS-II patient skin cells we have collected and banked over the years in our laboratory. In the first phase of the project, we generated progenitor brain cells, which are the so-called ‘induced-neural stem cells’ or iNSCs. This was key achievement to our project as having this progenitor brain cells that we could produce sufficient number of cells to carry on the proposed experiments. In addition, and most importantly, from the progenitor brain cells, we successfully produced very specific and mature brain cells as neurons – essential cells specialized to transmit information to other nerve cells, muscle, or gland cells. Using the iNSCderived neurons that are ultimately derived from MPS-II patients, we are now examining several disease processes associated with MPS-II. Through these experiments, we are observing differences in the neurons derived from MPS-II patients when compared to neurons from healthy individuals. These differences are in the way cells maintaining their calcium metabolism and also how they can recycle ‘waste’ – a process called ‘autophagy’. Interestingly, we are also investigating differences between nerves cells derived from MPS-II patients with the neuronopathic and non-neuronopathic forms of MPS-II. These differences will allow us to understand why some patients develop neurological problems and more rapidly progressive disease. We are currently writing a manuscript to be submitted to a peer-reviewed medical journal reporting these findings. In summary, in this project, we were established brain cells directly derived from skin cells from MPS-II patients that showed to be an excellent cell model to study the brain disease processes. In addition, these cell models can be used further to discover novel treatments for the neurological problems commonly seen in affected patients. This project was only possible due to the generous grant received from MPS Society Foundation.