ESACT spotlights gene therapy hopes for treating Rett Syndrome

Rett syndrome is a neurodevelopmental disorder that causes severe loss of motor function and intellectual disability. It is caused by mutations in the MeCP2 gene and predominantly affects females due to the mutation taking place in the X chromosome. Males who experience the same mutation do not survive infancy. 

Although MeCP2 genes are expressed throughout the human body, they are far more abundant in the brain than in other organs, and their numbers increase after birth. The MeCP2 genes that develop in the brain are critical for functioning. Bird said that scientists identified two methyl-CpG-binding (MBD) domains in MeCP2 genes that lead to 90% of Rett syndrome when a mutation occurs within them. The remaining 10% of Rett syndrome cases have been linked with c-terminal internal deletions. 

Bird discussed experiments in which scientists studied Rett syndrome in mice models. Without treatment, male mice with the characteristic MeCP2 mutations died within 12 weeks. Female mice survived, but experienced tremors and severely decreased motor function. Scientists then introduced affected mice with a gene therapy using an adeno-associated virus (AAV) viral vector. 

Bird showed side-by-side videos of a male mouse with Rett syndrome. In the first video, the mouse was almost entirely immobile, and Bird described it as being close to death. In the second video, the same mouse locomoted freely without any obvious trouble. Similar experiments showed improvement with female mice. 

Despite the gene therapy’s promising and even surprising ability to reverse motor dysfunction in mice, it is unclear if all aspects of Rett syndrome can be treated. Bird said that information regarding the return of cognitive function is lacking and requires further research. 

Two human trials began in 2022 for Rett syndrome gene therapies, with both scheduled to conclude in the fourth quarter of 2024. Bird said that press releases have shown promise but cautioned that scientists are awaiting results from the trials before they presume success.