FPWR’s Director of Research Programs, Dr. Theresa Strong, recently joined Daniel Levine on the RARECast podcast to discuss the GeneSYS initiative—FPWR’s translational research program focused on developing a targeted therapy for Schaaf-Yang syndrome (SYS). Below is a summary of the key points from their conversation and where the GeneSYS program stands today.
Understanding Schaaf-Yang Syndrome
Schaaf-Yang syndrome is an ultra-rare neurodevelopmental disorder caused by mutations in the MAGEL2 gene, located in the same chromosomal region associated with Prader-Willi syndrome (PWS). While PWS results from the loss of multiple genes in this region, SYS is caused by mutations in MAGEL2 that produce a truncated (shortened) protein.
Emerging research suggests that this altered protein may be toxic to cells—potentially explaining why SYS can present with more severe developmental challenges than PWS, despite affecting only a single gene.
SYS typically presents at birth with low muscle tone, feeding and breathing difficulties, and often requires NICU care. As children grow, many experience significant developmental delays, intellectual disability, autism spectrum features, endocrine differences, and disrupted sleep. There are only an estimated 400–500 diagnosed families worldwide.
The Rationale Behind GeneSYS
The GeneSYS initiative was launched to address a central hypothesis: if the truncated MAGEL2 protein is toxic, reducing or eliminating it could improve outcomes.
FPWR is pursuing an antisense oligonucleotide (ASO) strategy—an approach that uses short, synthetic strands of nucleic acids to reduce expression of a specific gene. ASOs have been successfully developed for other rare neurogenetic conditions, making this a promising and clinically validated platform.
Importantly, rare cases in which individuals are missing the MAGEL2 gene entirely, but do not show SYS symptoms, provide further support that the disease may stem from the toxic protein rather than simple loss of gene function.
Where the Program Stands Today
FPWR has partnered with academic scientists and contract research organizations (CROs) to:
- Identify promising ASO candidates that effectively reduce MAGEL2 expression
- Evaluate dose response and off-target effects
- Begin testing in cellular and animal models of SYS
The next critical steps include demonstrating that lowering the toxic protein leads to meaningful improvements in preclinical models. From there, the program would move toward IND-enabling safety and toxicology studies required before human trials.
While timelines in drug development are always uncertain, progress is steady. Importantly, the ASO approach is designed to work broadly across different SYS-causing mutations, potentially benefiting the majority of individuals with the condition.
Overcoming Key Challenges
Delivering therapies to the brain—particularly to the hypothalamus, where MAGEL2 is most active—remains a key scientific hurdle. Current thinking centers on intrathecal administration (delivery into the spinal fluid), though emerging delivery technologies are also being explored.
There are also financial and regulatory challenges unique to ultra-rare conditions. With only hundreds of individuals affected worldwide, traditional drug development models do not always fit. FPWR is actively exploring creative partnerships and funding strategies while preparing for early regulatory discussions.
The Role of Families
Families are central to GeneSYS. From funding early-stage research to helping define meaningful clinical outcomes—such as improvements in communication, cognition, sleep, and autism-related features—the SYS community is helping shape the path forward.
To date, much of this work has been made possible through family-driven fundraising efforts. As the program advances toward more expensive preclinical and regulatory stages, broader support and innovative development models will be essential.
GeneSYS represents a bold effort: applying cutting-edge genetic medicine to an ultra-rare condition that affects only a few hundred families worldwide. As Dr. Strong shared on RARECast, progress requires collaboration, creativity, and persistence—but the goal is clear: translating scientific insight into meaningful treatment for individuals with Schaaf-Yang syndrome.
We are grateful to Dr. Strong for representing the SYS community and to the families whose advocacy and support continue to drive this work forward. Listen here to the full RARECast episode!
Interested in making a meaningful impact in the SYS community? Connect with Nicci to learn how you can get involved!
