SMSRF Funds Yale Project Focused on Genetic Therapy Delivery – June 24, 2026
Building on the current foundation of SMS research and as part of our 5-Year Research Roadmap we are funding a two-year project with Yale University to test a new approach focused on restoring levels of RAI1, the key causal gene in SMS, in the brain. This work supports our broader goal of moving toward a first-in-human, disease-modifying clinical trial for SMS by 2030.
The Yale project addresses two major remaining challenges: delivery to the brain and control of RAI1 levels. Earlier SMSRF-funded research has shown that CRISPR activation, or CRISPRa, can increase RAI1 levels and improve some SMS-like features in mouse models. Those studies used viral delivery vectors, which can show proof of concept in mice, where the brain is much smaller. Translating that approach to humans remains challenging, especially if treatment needs to reach deeper or broader areas of the brain. The second challenge is control. RAI1 is dose-sensitive, meaning both too little and too much can cause problems.
That is why we are excited to partner with Dr. Jiangbing Zhou and Dr. Yong-hui Jiang at Yale. Their team has developed a novel non-viral brain delivery platform called STEP-RNP, which has shown promising brain delivery in other neurogenetic disease models. A non-viral approach may also allow for better control because it can be adjusted by dose and is designed for more temporary editor exposure, unlike viral approaches that may express therapeutic tools in cells for a long time. Over two years, the Yale team will first optimize the approach in brain-related cells and then test the best version in SMS mouse models.
The Yale team brings expertise in non-viral delivery, gene editing, neuroscience, genetics, and rare neurodevelopmental disorders. The significance of their platform is reflected in a $40 million NIH grant through the Somatic Cell Genome Editing program to advance this brain delivery technology toward clinical use for Angelman syndrome and H1-4 syndrome. Yale has described this work as a platform that could be applicable to many neurogenetic disorders. For us, this creates a very unique opportunity to test whether a major emerging platform for genetic brain disorders can also adapt to the specific challenge of restoring RAI1 levels in SMS.
This project marks an important milestone in the Foundation’s 5-Year Research Roadmap as one of our first investments specifically focused on restoring RAI1 function—the gene at the center of SMS. As the field advances, RAI1 restoration is emerging as one of the most compelling pathways toward a future disease-modifying treatment. By supporting this work, we are investing in research that aims to address the underlying cause of SMS and move us closer to our goal of a first clinical trial by 2030.
It would not be possible without years of research in the SMS field and the continued contributions of our community. We are deeply grateful to you – our families, donors, researchers, and partners – who are are making this work possible and helping us keep moving toward disease-modifying treatments for SMS.
