Rett Syndrome: Crossing the Threshold to Clinical Translation

Abstract

Lying at the intersection between neurobiology and epigenetics, Rett syndrome (RTT) has garnered intense interest in recent years, not only from a broad range of academic scientists, but also from the pharmaceutical and biotechnology industries. In addition to the critical need for treatments for this devastating disorder, optimism for developing RTT treatments derives from a unique convergence of factors, including a known monogenic cause, reversibility of symptoms in preclinical models, a strong clinical research infrastructure highlighted by an NIH-funded natural history study and well-established clinics with significant patient populations. Here, we review recent advances in understanding the biology of RTT, particularly promising preclinical findings, lessons from past clinical trials, and critical elements of trial design for rare disorders.

Keywords: MECP2; clinical trials; epigenetics; gene therapy; neurodevelopmental disorders; preclinical models.

Figure 1. Therapeutic Targets and Potential Pharmacological Strategies Currently Being Explored in Animal Models for the Treatment of Rett Syndrome

Underlined headings indicate therapeutic targets; compounds that have been reported in the literature to be effective in improving behavioral outcome measures or physiological function in vivo are shown in italics (see Table S1 in the supplemental information online for the figure references).

Figure 2. Neural Circuit Dysfunction in the Methyl-CpG-Binding Protein 2 (Mecp2) Mutant Brain

Colors indicate brain regions in which Mecp2 mutant mice exhibit a shift in either neuronal or synaptic activity towards decreased (blue) or increased (red) excitation compared with wild-type controls. This schematic summarizes findings from numerous laboratories and is based on electrophysiological recordings of intrinsic neuronal activity, synaptic activity, and/or population activity, as well as Fos mapping of neuronal activity. Abbreviations: 3 V, third ventricle; 4 V, fourth ventricle; CA1, cornu ammonis; cc, corpus callosum; Cg, cingulate; DG, dentate gyrus; IL, infralimbic cortex; LC, locus coeruleus; LSN, lateral septal nuclei; M, motor cortex; nAC, nucleus accumbens; nTS, nucleus of the solitary tract; OB, olfactory bulb; PAG, periaqueductal gray; Pir, piriform nucleus; PrL, prelimbic cortex; RS, retrosplenial cortex; S, somatosensory cortex; V, visual cortex; VLM, ventrolateral medulla.

Figure 3. High-Content Small-Molecule Screening Strategy to Detect Methyl-CpG-Binding Protein 2 (Mecp2) Reactivation

Neurons harvested from Embryonic day (E)15.5 embryos produced in matings between hemizygous Mecp2-GFP males and wild-type females are used to screen for Mecp2 de-inactivating compounds. Of the neurons derived from female embryos, approximately 50% will be GFP+ due to random X chromosome inactivation (XCI). Positive hits result in an increase in the proportion of GFP-labeled neurons. Neurons derived from nontransgenic male embryos serve as negative controls. GFP reporter mice are available from Jackson Laboratories (Mecp2^tm3.Bird/J; Reference #014610).