The GeneSYS project continues to make meaningful progress toward a targeted treatment for Schaaf-Yang Syndrome (SYS), a rare genetic condition caused by a mutation in the MAGEL2 gene. While there is still important work ahead, recent developments are sharpening the scientific focus and guiding the next critical steps toward a potential clinical trial.
Understanding the Problem: MAGEL2 and the Nucleus
The core hypothesis driving the GeneSYS program is centered on what happens when MAGEL2 carries a truncating mutation. Under normal conditions, the MAGEL2 protein performs essential functions both inside and outside of a cell’s nucleus. However, when mutated, the protein cannot be as efficiently moved out of the nucleus, accumulates there, and begins to disrupt normal cellular activity.
This misbehavior may help explain why individuals with Schaaf-Yang Syndrome often experience more severe symptoms than those with Prader-Willi syndrome, who don’t have any MAGEL2 protein at all. Researchers believe the truncated MAGEL2 protein causes harm when it builds up in the nucleus, and that reducing its presence there could significantly improve cellular health.
The Role of Oligonucleotides
To address this, researchers are testing antisense oligonucleotides (ASOs), designed to reduce or eliminate the harmful mutated MAGEL2. Through extensive analysis and testing, the team has identified several promising oligonucleotide candidates and evaluated their potency to determine how effectively they reduce the mutated protein.
We have moved the most effective candidates into the next phase of testing: off-target analysis. This crucial step will evaluate side effects, such as unintentionally silencing other genes. The goal is to identify safe, precise, and clinically viable candidates that specifically target the harmful MAGEL2 mutation without disrupting healthy genetic function.
Determining the Path Forward
With these results in hand, the research team will face the important question of what comes next? Several potential paths are being evaluated. Researchers are considering further studies in stem cells and rat models of SYS to demonstrate that knocking down mutated MAGEL2 improves overall health.
A critical piece of this phase will be determining what outcomes should be measured — how to clearly demonstrate that reducing the harmful MAGEL2 protein leads to meaningful biological improvement. Once this data shows clear benefit and safety, the project can advance to toxicology studies, which are a necessary step before initiating any human clinical trial.
Collaboration and Expertise Guide the Next Phase
To thoughtfully determine the best direction forward, FPWR will convene several leading investigators in the field to evaluate the most effective path forward. This collaborative approach will ensure that every decision is grounded in both scientific rigor and the ultimate goal of bringing tangible treatments to individuals and families affected by SYS.
Looking Ahead: A Deep Dive with Dr. Theresa Strong
FPWR Director of Research Programs, Theresa Strong, and Research Program Manager, Marc Ridilla, will host a GeneSYS Update Town Hall in January to provide a comprehensive update on the GeneSYS project, walk through the current data, and explain the upcoming steps in detail. This will also be an opportunity for families to ask questions, gain clarity, and engage directly with the science driving this work forward. Register here for the GeneSYS Update Town Hall.
While there is still critical research to complete, each phase of GeneSYS brings us closer to a potential therapeutic approach that could change the trajectory of Schaaf-Yang Syndrome. The steady momentum of this project reflects not only scientific innovation but also the enduring partnership between researchers, clinicians, and the families whose lives are shaped by these rare conditions.
