Novel MeCP2 Gene Therapy is Effective in a Multicenter Study using Two Mouse Models of Rett Syndrome and is Safe in Non-human Primates.

The AAV9 gene therapy vector presented in this study is safe in mice and non-human primates and highly efficacious without causing overexpression toxicity, a major challenge for clinical translation of Rett Syndrome gene therapy vectors to date. Our team designed a new truncated methyl CpG binding protein 2 (MeCP2) promoter allowing widespread expression of MeCP2 in mice and non-human primates after a single injection into the cerebrospinal fluid without causing overexpression symptoms up to 18 months post injection. Additionally, this new vector is highly efficacious at lower doses compared to previous constructs as demonstrated in extensive efficacy studies performed by two independent laboratories in two different Rett syndrome mouse models carrying either a knockout or one of the most frequent human mutations of MeCP2. Overall, data from this multicenter study highlights the efficacy and safety of this gene therapy construct, making it a promising candidate for first in human studies to treat Rett syndrome.