AAV gene therapy for Marinesco-Sjögren syndrome: optimizing delivery, expression and therapeutic timing for clinical translation

Marinesco-Sjögren syndrome (MSS) is a rare genetic disorder that begins in early childhood and currently has no cure. Children with MSS typically experience difficulty walking, poor muscle tone, and coordination problems within the first months of life. As the disease progresses, movement and strength decline, but symptoms often stabilize later in life. Because individuals can live into adulthood, treatments that slow or stop disease progression – even after symptoms begin – could significantly improve quality of life. MSS is caused by mutations in the SIL1 gene, which plays a key role in maintaining cell health, particularly in the brain and muscles. Our research aims to develop a gene therapy that delivers a healthy copy of SIL1 using a harmless virus called AAV (adeno-associated virus). Early experiments showed that injecting AAV-SIL1 into the brain of newborn mice with MSS prevents disease symptoms. In this project, we will optimize the therapy for delivery through the bloodstream, a less invasive and more practical method for patients. We will test different gene versions and regulatory elements to ensure safe and effective treatment. We will also determine how late the therapy can be given while still providing benefit. Finally, we will evaluate advanced AAV variants that can enter the human brain, using mice genetically modified to better reflect the human condition. This work will generate critical data on the safety, timing, and effectiveness of AAV-SIL1 therapy and support its future translation into clinical trials – offering new hope to individuals and families affected by MSS.