Neurobiologically-based treatments in Rett syndrome: opportunities and challenges

Abstract

Introduction: Rett syndrome (RTT) is an X-linked neurodevelopmental disorder that primarily affects females, typically resulting in a period of developmental regression in early childhood followed by stabilization and severe chronic cognitive, behavioral, and physical disability. No known treatment exists beyond symptomatic management, and while insights into the genetic cause, pathophysiology, neurobiology, and natural history of RTT have been gained, many challenges remain. Areas covered: Based on a comprehensive survey of the primary literature on RTT, this article describes and comments upon the general and unique features of the disorder, genetic and neurobiological bases of drug development, and the history of clinical trials in RTT, with an emphasis on drug trial design, outcome measures, and implementation. Expert opinion: Neurobiologically based drug trials are the ultimate goal in RTT, and due to the complexity and global nature of the disorder, drugs targeting both general mechanisms (e.g., growth factors) and specific systems (e.g., glutamate modulators) could be effective. Trial design should optimize data on safety and efficacy, but selection of outcome measures with adequate measurement properties, as well as innovative strategies, such as those enhancing synaptic plasticity and use of biomarkers, are essential for progress in RTT and other neurodevelopmental disorders.

Keywords: MECP2; Rett syndrome (RTT); fragile X syndrome (FXS); outcome measure.

Figure 1.

Model of neuronal pathology in Rett syndrome based on dendritic development in the prefrontal cortex. (a) During normal development, onset of MeCP2 expression coincides with early neuronal differentiation. Levels of MeCP2 function, depicted as intensity of blue label, increase steadily after afferents (e.g., monoamines) begin to influence cortical neuronal differentiation. Direct targets of MeCP2, such as BDNF, in conjunction with other synaptic signals have a particularly strong effect on the process of dendritic pruning. (b) Marked reduction in MeCP2 function and deficient afferent input in neurons carrying a MeCP2 mutated allele impairs appropriate dendritic expansion. The abnormality extends and worsens during dendritic pruning because of the abnormally high levels of MeCP2 targets (i.e., BDNF) and additional neurotransmitter disturbances (glutamate receptor activity). The ultimate neuronal phenotype is characterized by a smaller cell with markedly decreased MeCP2 expression and dendritic arborizations. RTT neurons carrying the normal allele are also affected. Because of decreased local (neighboring neurons with mutated allele) and distant (monoaminergic) synaptic signals, and secondary abnormalities such as increases in BDNF and glutamatergic activity, these neurons are unable to reach normal soma and dendritic size and remain as low-expressing (MeCP2^lo) cells. GFs: growth factors. Used with permission from Ref. [34].