A Gene Therapy to Treat the FOXG1 Brain Disorder

Soo-Kyung Lee, a neurodevelopmental biologist from the State University of New York at Buffalo, built her career studying transcription factors important for brain development and understanding how their dysregulation leads to human disease. When her daughter, Yuna Lee, exhibited neurological symptoms as a baby, Soo-Kyung Lee’s life and research pivoted in response to her child’s diagnosis.

“[She had] a lot of brain scans, then blood work, and many different tests. [The results] eerily resembled some disorders that I had studied indirectly,” said Soo-Kyung Lee.

Fourteen years ago, sequencing results confirmed that Yuna Lee’s condition was caused by a mutation in one copy of the forkhead box protein G1 (FOXG1) gene. It encodes a transcription factor that at the time was newly linked to a rare congenital variant of a neurodevelopmental condition called Rett syndrome.¹ In response, Soo-Kyung Lee joined forces with her husband, neuroscientist Jae Lee, to start a laboratory focused on understanding and curing this disorder. Since then, they and other researchers have fleshed out FOXG1’s important role in early brain development in utero.² The Lees’ recent work, published in Molecular Therapy Methods & Clinical Development, describes a gene therapy for FOXG1 syndrome that repaired some associated brain abnormalities in young mice.³ This work suggests that while genetic neurodevelopmental disorders like FOXG1 syndrome impart their consequences in the womb, it may not be too late to repair brain defects after birth.

Humans heterozygous for FOXG1 pathogenic variants, which typically arise from de novo mutations, display severe brain structural deficits, such as microcephaly, delayed myelination along axons, and a malformed dentate gyrus, which is important for cognitive functions including memory. Patients with FOXG1 syndrome also have an underdeveloped corpus callosum—a thick nerve fiber bundle that connects and transmits information between the right and left sides of the brain, playing a role in movement, cognition, and vision.² These structural features lead to symptoms such as seizures, intellectual and speech disabilities, lack of movement control, sleep disorders, and excessive crying. “When my daughter was young, she cried all the way through the night, every night, and I had to take her outside to console her,” said Soo-Kyung Lee. “I was thinking, what will my neighbors say?…I hear this concern a lot from other parents as well.”

[The corpus callosum] was restored, and that was really a wow moment. It exceeded our expectations, and that's not something that happens every day.
– Soo-Kyung Lee, State University of New York at Buffalo

Individuals with FOXG1 syndrome require constant care to fulfill their basic needs, and there is no treatment, only medicines for symptom management. Soo-Kyung Lee hoped to change that through gene therapy. However, some had doubts that because of FOXG1’s role in brain development in utero, administering a therapy after birth may not have a noticeable effect. “My colleagues told me that, ‘it's great that you are working on the gene that cause your daughter's problems, but the chance of you finding cure is very slim’,” said Soo-Kyung Lee.

The researchers found that FOXG1 is continuously expressed and functional in the brains of postnatal mice. This suggested that upping the FOXG1 dose at a later stage could be effectual. Lee’s team developed a gene therapy that delivers a functional gene via an adeno-associated viral (AAV) vector, normalizing FOXG1 protein levels, and tested it in a mouse model of FOXG1 syndrome.

After injecting the gene therapy into the brains of day-old mice, the researchers analyzed their brains a month later to determine if there were any improvements. Despite concerns about the feasibility of repairing structural deficits that developed before birth, the researchers observed encouraging results, including changes in brain regions responsible for language and memory in humans.

“The really pleasant surprise is that we were able to rescue these phenotypes that are caused by earlier function of the FOXG1 gene,” said Soo-Kyung Lee. “[The corpus callosum] was restored, and that was really a wow moment. It exceeded our expectations, and that's not something that happens every day.” In addition, the researchers found that the number of cortical neurons increased, myelination was rescued, and dentate gyrus abnormalities were reversed.

“The capability to revert that even in a more advanced brain, it's quite amazing,” said Alysson Muotri, a neuroscientist from the University of California, San Diego who also works on FOXG1 syndrome but was not involved in this study. “I congratulate the authors because [the study] is a tour de force. This is definitely on the right track for a clinical application.”

The team’s next steps are to further optimize their AAV vector for human clinical trials. The researchers are optimistic about their therapy’s future because they have a solid foundation understanding the basics of neurodevelopmental disorders. “Coming from basic research to drug development really facilitated this process by having good science knowledge underlying the disease,” said Soo-Kyung Lee. “That, I think, is critical for drug development.”