During the recent GeneSYS Update Town Hall, FPWR shared encouraging progress on the GeneSYS project, a research initiative focused on developing a targeted therapeutic approach for Schaaf-Yang syndrome (SYS). While this work is still in the early stages, the updates represent an important milestone and a strong foundation for what comes next.
In individuals without Schaaf-Yang syndrome, the MAGEL2 gene produces a full-length, functional protein that plays an important role inside the cell. In individuals with SYS, mutations in MAGEL2 cause the protein to be truncated, meaning it is shorter than it should be.
This missing portion of the protein turns out to be critical. Without it, MAGEL2 is misdirected inside the cell and accumulates in the nucleus, rather than remaining primarily in the cytoplasm where it normally functions. Researchers believe this abnormal buildup interferes with normal cellular function and contributes to the symptoms seen in Schaaf-Yang syndrome.
Importantly, there are a small number of individuals known to be missing the MAGEL2 gene entirely who show few or no symptoms. This observation has helped shape the central hypothesis behind GeneSYS:
It may be more harmful for cells to have a dysfunctional, truncated MAGEL2 protein than to have no MAGEL2 protein at all.
To test this hypothesis, the GeneSYS project is using a well-established therapeutic approach known as antisense oligonucleotides (ASOs). ASOs are short pieces of genetic material designed to bind to a specific RNA sequence and prevent a protein from being made.
ASOs are already used in other genetic and neurological disorders, including Huntington’s disease, and the FDA is familiar with their development pathway. In GeneSYS, ASOs are being designed to selectively reduce or eliminate production of the mutated MAGEL2 protein.
A key advantage of this approach is that the same ASO strategy could work across all SYS mutations, rather than requiring a different treatment for each individual mutation.
The GeneSYS team has completed, or is nearing completion of, the first five standardized phases of ASO development:
Phase 1: ASO Design
Hundreds of possible ASOs were computationally designed, with the top 100 selected for synthesis based on predicted effectiveness and safety.
Phase 2: Assay Development
Researchers established a sensitive laboratory test to accurately measure MAGEL2 levels in human neurons.
Phase 3: Screening
All 100 ASOs were tested in human neuronal cells to see how effectively they reduced MAGEL2 expression.
Phase 4: Dose Optimization
The most promising ASOs were tested at multiple doses to confirm that higher doses resulted in greater MAGEL2 reduction, demonstrating predictable and controllable behavior.
Phase 5: Safety and Specificity (in progress)
The top-performing ASOs are being evaluated to ensure they do not affect other genes, confirming that their effects are specific to MAGEL2. Data analysis is expected to conclude imminently.
So far, the results are very encouraging. Several ASOs reduced MAGEL2 expression by 50–80%, a strong signal that the strategy is working as intended.
At this stage, all testing has been done only in cells grown in the laboratory, using human neurons derived from neurotypical donors. No children or individuals with Schaaf-Yang syndrome have been tested, and no clinical trials are underway yet.
The next critical question is not just whether MAGEL2 can be reduced, but whether reducing it actually improves cell health in SYS models.
The next phase of GeneSYS will focus on answering that question through carefully designed experiments:
Testing ASOs in cellular models that carry Schaaf-Yang mutations
Identifying measurable markers that distinguish unhealthy SYS cells from healthy cells
Determining whether ASO treatment shifts SYS cells toward more typical function
Eventually, this work may extend to animal models, where researchers can study effects on behavior, movement, feeding, and cognition; things that cannot be assessed in cells alone.
In parallel, FPWR is supporting complementary projects that strengthen the GeneSYS pipeline, including advanced cellular assays, rodent MAGEL2 studies, and ASO development tailored to animal models.
Progress like this is only possible because of community involvement. Families can continue to support this work by:
Participating in the Global Schaaf-Yang Syndrome Registry, which helps families and researchers better understand the full range of SYS development and symptoms
Contributing to the CombinedBrain biorepository when opportunities are available
Continuing to fundraise and advocate for Schaaf-Yang research
GeneSYS is still early in the therapeutic development journey, but the project has moved efficiently and deliberately, with strong scientific rationale and promising early data. Each completed phase brings us closer to understanding whether this approach can truly change outcomes for individuals with Schaaf-Yang syndrome. We are grateful to the families, researchers, and supporters who make this work possible, and we will continue to share updates as the science moves forward.
This 36-minute recorded presentation walks you through the science behind the project, current progress, and what comes next for GeneSYS. Click below or watch the recording on our YouTube channel.