Washington University School of Medicine in St. Louis is one of only ten sites in the world participating in a pioneering clinical trial evaluating TSHA-102, an investigational gene therapy for the treatment of Rett syndrome, a severe neurodevelopmental disorder primarily affecting girls. The REVEAL Phase 1/2 clinical trial represents a significant advancement in the quest to find an effective treatment for this debilitating disease. Pediatric neurologists Robin Ryther, MD, PhD, Judith Weisenberg, MD, and Oleg Lobanov, MD, PhD, lead the trial team at WashU Medicine.
“This clinical trial is critically important because Rett syndrome is caused by genetic mutations. To effectively alter the course of the disease, we need to address the underlying genetic issue,” said Weisenberg, professor of neurology at WashU Medicine. “We believe this method could potentially provide meaningful therapeutic benefit to individuals with Rett syndrome, though we must rigorously evaluate its safety and efficacy first.”
Rett syndrome results from mutations in the methyl CpG binding protein 2 (MECP2) gene, leading to severe neurodevelopmental disabilities. The gene therapy being evaluated in the trial aims to introduce a functional copy of the MECP2 gene into patients’ central nervous systems using an adeno-associated virus
“Rett syndrome presents a unique challenge. Insufficient MECP2 causes Rett syndrome, while an excess leads to MECP2 duplication syndrome. We must achieve precise balance,” said Ryther, associate professor of neurology at WashU Medicine.
This trial is one of only two of its kind currently underway in the U.S., with WashU Medicine being the third active site to offer this novel treatment. As of the time of this article, several adult, adolescent and pediatric patients were dosed in Canada and the U.S. WashU Medicine dosed its first patient on January 28, 2025. Ryther said the use of this therapy for Rett syndrome “is still very new, and gathering data is ongoing. The aim is to comprehensively evaluate the potential of this gene therapy to modify or halt the progression of Rett syndrome in human patients.”
Patients aged 5 to 8 years will be recruited from WashU Medicine’s Rett spectrum clinic, which provides care for approximately 120 patients with Rett syndrome. The trial demands significant commitment from participating families, including the possibility of relocating to St. Louis, Missouri, for several months due to the frequency of hospital visits.
“The first three months of the study are particularly intensive,” Weisenberg said. “Many families may need to temporarily relocate to ensure regular attendance at hospital visits and fulfill the trial’s requirements.”
The gene therapy is injected as a single intrathecal dose directly into the spinal fluid, which requires coordination with interventional radiology and anesthesia.
“Patients will undergo immunosuppression to decrease immune response and prevent rejection of the new DNA, necessitating significant lifestyle adjustments,” Ryther said. This intensive observation and treatment period is crucial to monitor the therapy’s immediate effects and ensure patient safety.
“Our approach targets the central nervous system, which has potential to impact the core features of Rett Syndrome,” Ryther said. “Only through this trial can we understand the full scope of the therapy’s potential.”
The trial is funded and conducted by Taysha Gene Therapies, Inc., a Dallas-based biotechnology company focused on advancing gene therapies for central nervous system disorders. WashU Medicine receives additional support from charitable donations and contributions from grateful families.
“We are deeply appreciative of the support that enables us to undertake this extensive project,” Ryther said. “The combination of corporate funding and philanthropic contributions is essential to advancing this critical research.”
As the trial progresses, the collaborative efforts of the medical team and participating families are crucial to its success. Weisenberg emphasized that “the progress of this trial is a testament to the dedication of our researchers, clinicians and families.” The trial not only represents a critical step for Rett syndrome but also positions WashU Medicine at the forefront of genetic therapy research for rare diseases. “The lessons learned here will have far-reaching implications,” Weisenberg said.
The WashU Medicine team remains hopeful that this innovative trial will lead to a new treatment for Rett syndrome. Ryther said the trial “represents a significant step in advancing treatments for rare genetic disorders, and we are committed to pushing the boundaries of medical science to improve patient outcomes.”
For more information on the clinical trial, please visit the official clinical trial registry at ClinicalTrials.gov.