Dr. Blewitt has been working on a gene therapy approach for PWS that targets a factor called SMCHD1, which normally switches off the PWS genes. Here, her group will test whether removing SMCHD1 allows the PWS-regions genes to be expressed and improve symptoms in a PWS mouse model with an imprinting center deletion.
Dr. Theresa Strong, Director of Research Programs, shares details on this project in this short video clip.
One of the major challenges for PWS is the lack of a treatment that has the potential to improve many or all symptoms experienced by patients. Such a disease-modifying treatment would be a game-changer for patients and their families. The best way to create such a treatment is to target the underlying cause of disease, the lack of expression of the PWS genes. In our project we are seeking to test whether targeting a factor called SMCHD1, which switches off PWS genes, is effective at allowing these genes to be switched back on again so that patients use their own PWS genes to treat disease.
Our approach is to use living models of PWS partnered with genetic tools to target SMCHD1. We will test the effect of removing SMCHD1 on how the PWS genes are expressed and the effect on the symptoms in this model of PWS. Our hypothesis is that targeting SMCHD1 will activate all genes across the PWS cluster and ameliorate symptoms observed in this PWS model.
Our proposed work builds on our existing data that suggests targeting SMCHD1 is a valid approach for developing a disease-modifying treatment for PWS, but our project goes further in specifically using a PWS model that best capitulates the loss of expression of all PWS genes, rather than just one or two. This approach is important as it best models what occurs in the vast majority of PWS patients.
This research will provide critical proof of principle data that will be valuable for our current world-first drug development program for SMCHD1. We have developed chemicals that inhibit SMCHD1 and could be developed into drugs to treat patients, with significant industry investment. The data generated by this project will derisk such investment and therefore encourage the next stage for our drug development program. In essence, with successful completion of this project we will increase the likelihood of obtaining the investment required to create drugs to enter clinical trials in PWS patients.
Beyond creating valuable data, this project will also mean that our team has experience with this specific PWS model, and therefore will be primed to test the effect our SMCHD1 inhibitor chemicals in exactly the same model. Therefore, this project lays the foundation for therapeutic development, specifically for a potentially disease-modifying treatment for PWS.