58. Rett Syndrome Is Reversible and Treatable by MeCP2 Gene Therapy into the Striatum in Mice

Abstract

Introduction and aims: Mutations in the methyl-CpG-binding protein 2 (MeCP2), which binds methylated DNA and regulates gene expression, cause Rett syndrome (RTT). RTT is a neurodevelopmental disorder characterized by normal early psychomotor development, followed by the loss of psychomotor skills, and by the onset of stereotyped hand movement and of gait disturbances; no effective therapy has been developed for the RTT. MeCP2 gene therapy may be a potential candidate for effective therapy for the RTT, however, due to no experimental trial, the potential effectiveness of conducting MeCP2 gene therapy is unknown from the following biological viewpoints. The expression of MeCP2 begins during embryonic development and the expression levels of MeCP2 are high in all neurons in normal humans and mice after birth, whereas the neurological functions that MeCP2 regulates remain largely unknown. Thus, it is not possible to hypothesize whether the expression of an intact MeCP2 gene can, following the onset, modulate pre-established neurological symptoms. An additional obstacle is the fact that all of the current vectors allow only local gene delivery, although MeCP2 is expressed in all neurons in normal humans. Here we show that local delivery of the MeCP2 gene into the striatum of MeCP2-deleted mice remarkably improved the pre-established symptoms of impaired locomotion and self-injury.