Preclinical Milestones in MECP2 Gene Transfer for Treating Rett Syndrome

Abstract

<b><i>Background:</i></b> Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2). After gene transfer in mice, exogenous MeCP2 expression must be regulated to avoid dose-dependent toxicity. <b><i>Summary:</i></b> The preclinical gene therapy literature for treating RTT illustrates a duly diligent progression that begins with proof-of-concept studies and advances toward the development of safer, regulated <i>MECP2</i> viral genome designs. This design progression was partly achieved through international collaborative studies. In 2023, clinicians administered investigational gene therapies for RTT to patients a decade after the first preclinical gene therapy publications for RTT (clinical trial numbers NCT05606614 and NCT05898620). As clinicians take on a more prominent role in <i>MECP2</i> gene therapy research, preclinical researchers may continue to test more nuanced hypotheses regarding the safety, efficacy, and mechanism of <i>MECP2</i> gene transfer. <b><i>Key Message:</i></b> This review summarizes the history of preclinical <i>MECP2</i> gene transfer for treating RTT and acknowledges major contributions among colleagues in the field. The first clinical injections are a shared milestone.