A team of researchers at the University at Buffalo has developed a viral gene therapy that has successfully reversed certain brain abnormalities in baby mice with FOXG1 syndrome. This is a promising advancement in the potential treatment of children with this severe neurodevelopmental disorder. The study, published in Molecular Therapy Methods &, outlines the use of adeno-associated virus 9 (AAV9) to deliver the FOXG1 gene to the affected mice.Clinical Development. According to the study, a postnatal injection of the therapy in day-old mice was able to improve a variety of abnormalities, including those in brain regions responsible for language, memory, and social interaction. Soo-Kyung Lee, PhD, and Jae Lee, PhD, who led the study, stated that these findings demonstrate the effectiveness of AAV9-based gene therapy as a potential treatment for FOXG1 syndrome and other neurodevelopmental disorders with similar brain malformations.The professor in the department stated, “Our research demonstrates the importance of our approach during the postnatal period, which is a crucial time for intervention.”
Yuna, the Lees’ teenage daughter, was diagnosed with FOXG1 syndrome when she was 2 years old. The researchers have become leading experts on the condition and lead the UB’s FOXG1 Research Center (FRC). This center, established earlier this year, along with the recent study, is funded by the FOXG1 Research Foundation.
The study was co-led by Kathrin Meyer, PhD, who is the principal investigator at Nationwide Children’s Hospital.Columbus, Ohio. Other researchers from the University of Pennsylvania and Samsung Medical Center in Seoul, South Korea also made significant contributions to the study.
Correcting structural abnormalities
FOXG1, a master regulator gene, is crucial for early brain development. When it is impaired, it can lead to significant abnormalities in brain structure.
Prior research by the Lees showed that the FOXG1 gene and protein remain active in mice after birth. This led them to investigate whether restoring FOXG1 levels could reverse some of the abnormalities associated with FOXG1 syndrome.
These abnormalities encompassfailure to fully develop the corpus callosum, the bundle of nerves that connect the brain’s two hemispheres and help integrate sensory and motor information with social interaction, executive function, and language.
It is believed that correcting the corpus callosum after birth would be very challenging since it develops before birth. However, when the Lee team injected their viral gene therapy into mice after birth, it reconnected the callosal axons and restored the callosal nerves, significantly improving the corpus callosum.
The therapy also enlarged the dentate gyrus, which is the main gateway for input formation into theThe rest of the hippocampus, which is important for memory, is one of the few areas of the brain that continues to generate new neurons as mammals age. This makes it an important target for postnatal treatments. Additionally, the treatment improved the function of the brain areas involved in the speed of communication between neurons.
Oligodendrocytes are the cells responsible for myelination, which is the process of insulating nerves to allow for rapid transmission of information. Brains affected by FOXG1 often have a high number of oligodendrocyte precursor cells (OPC) but delayed myelination.
The study found that the treatment normalized the number of OP cells.
The researchers expressed their excitement about the successful restoration of myelination in Cs while conducting their study. They believe that this study lays a strong groundwork for the progression of gene therapy to be used in human clinical trials.
The researchers stated, “We are thrilled to see the complete improvement of brain structure abnormalities in our mouse model during this study. This represents a significant advancement in our research. With these promising results, we are eager to progress with the AAV9 compound towards human clinical trials, with the hope of extending these breakthroughs to benefit children with FOXG1 syndrome.”
