Rett syndrome (RTT) is a severe neurodevelopmental disorder (NDD), characterized by multiple impairments, which affects predominantly females. Until March 2023, no drug treatments were available for RTT’s core symptoms. The recent approval of trofinetide by the FDA and the beginning of gene therapy trials represent major achievements with profound implications. They also represent a culmination of a process that began before the identification of mutations in the MECP2 gene as the main cause of RTT.

Knowledge on the pathology and neurochemistry of RTT and development of mouse models of Mecp2 deficiency have been instrumental in both identifying and validating new treatments. Availability of disorder’s natural history data has also been a major contributor. Efforts in the U.S.A., Europe, and Australia at characterizing the range and evolution of neurobehavioral and systemic manifestations of RTT have allowed the most adequate selection of trial participants and the development of outcome measures.

The success of trofinetide’s studies, in combination with positive results of the mecasermin (recombinant human IGF-1) and blarcamesine (sigma-1 receptor agonist) drug development programs, support strategies targeting multiple cell signalling pathways and endogenous homeostasis for ameliorating the numerous and greatly impairing symptoms of RTT, even in adults. These improvements have been observed despite short duration treatments and suboptimal endpoints. Consequently, drug trials have facilitated the testing of therapies with even greater potential: attempts at correcting the genetic defect underlying RTT. Early information supports the safety of gene therapy in RTT; however, more time will be needed to determine their efficacy. The approval of a drug targeting core features of RTT has changed the stakeholders’ mindset, becoming not the end of a pathway but rather the first step in developing new treatments (even combining approaches). This and other learned lessons should be carefully examined by others in the NDD field.

Keywords: Rett syndrome, neurodevelopmental disorders, drug trials, gene therapy, mouse models, natural history, outcome measures