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:

• Rett syndrome (RTT)
• MECP2
• fragile X syndrome (FXS)
• outcome measure

Article highlights

• RTT is a unique neurodevelopmental disorder characterized by a dynamic clinical course with complex multisystem involvement.

• Insights into the pathophysiology, neurobiology, and natural history of RTT are providing a foundation upon which to develop and test a variety of novel pharmacologic interventions.

• RTT and other neurodevelopmental disorders have overlapping therapeutic targets and face similar challenges with respect to clinical trial implementation.

• Development of biomarkers and other validated outcome measures is critically important for RTT drug trials.

• Innovative strategies in trial design will be necessary to continue to translate preclinical findings into effective treatments for persons with RTT and other rare disease populations.

This box summarizes key points contained in the article.

Declaration of interest

WE Kaufmann is a consultant to Neuren, Newron, EryDel, Marinus, GW, Eloxx and Edison Pharmaceuticals. SA Skinner is an investigator on the current Neuren Pharmaceuticals clinical trial for Rett syndrome (NNZ-2566). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

The authors of this paper received grant support from the NIH [U54 HD061222] and from Rettsyndrome.org [2907 and 3105].