Dr. Gersbach’s earlier success in unsilencing maternal copies of PWS genes in developing neurons will now be adapted to work in mature neurons. He will identify regulatory features hindering unsilencing in mature neurons and test combination therapies to enable stable reactivation in PWS patients of any age.
This project is focused on developing a gene therapy for PWS by carefully turning on genes that are naturally present but “switched off” in every person with the syndrome. Our innovative approach uses special molecular tools to reactivate the healthy set of PWS genes that every person with PWS already carries, without making permanent, irreversible changes to a person’s DNA. We have already shown that these silenced genes can be safely and durably reactivated in patient-derived stem cells using our precise epigenetic tools, and that this effect can persist as these stem cells are turned into brain cells, demonstrating the feasibility of our approach. This raises the exciting possibility of a one-time, long-lasting treatment that addresses PWS at its source. The next step—and the focus of this proposal—is to learn how to achieve the same effect directly in brain cells, because these are central to PWS symptoms. We will use advanced techniques to map out what is keeping the maternal genes switched off in neurons and then design combination treatments to unlock these barriers. If we succeed, this new therapy could help correct the underlying cause of PWS with a treatment that would need to be given only once but could restore vital gene activity for a lifetime.
What makes this research important is its focus on a permanent, one-time therapy that works with the body’s own genes—offering the potential to address PWS at its source, rather than just managing symptoms. If the project is successful, the groundwork laid here will guide the final steps needed to bring this therapy closer to clinical trials and, eventually, make it available to patients. The insights, data, and reagents we generate will be shared with the broader research community to accelerate progress toward clinical trials and benefit everyone affected by PWS, regardless of their genetic subtype. Importantly, even if we encounter unexpected challenges, we will gain valuable information about how to overcome genetic silencing, informing not just PWS care but also other related genetic and imprinting disorders.
In summary, this project aims to lay the scientific and technical foundation for a precise, lasting cure for PWS—one that could be administered once, with effects that last a lifetime. This would have a transformative impact for families living with PWS by moving from lifelong symptom management to targeting the underlying cause of the disorder. Through collaborative effort and open sharing of results, our work will directly move the field closer to the first effective, safe gene therapy for PWS, and create solutions for other rare diseases where “switching on” the body’s own healthy genes could restore hope and health.