Treating Rett syndrome: from mouse models to human therapies

Abstract

Rare diseases are very difficult to study mechanistically and to develop therapies for because of the scarcity of patients. Here, the rare neuro-metabolic disorder Rett syndrome (RTT) is discussed as a prototype for precision medicine, demonstrating how mouse models have led to an understanding of the development of symptoms. RTT is caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2). Mecp2-mutant mice are being used in preclinical studies that target the MECP2 gene directly, or its downstream pathways. Importantly, this work may improve the health of RTT patients. Clinical presentation may vary widely among individuals based on their mutation, but also because of the degree of X chromosome inactivation and the presence of modifier genes. Because it is a complex disorder involving many organ systems, it is likely that recovery of RTT patients will involve a combination of treatments. Precision medicine is warranted to provide the best efficacy to individually treat RTT patients.

Fig. 1

Symptom severity in RTT is influenced by mutation status, XCI pattern, and modifier genes. a Of the 8 most common RTT-causing MECP2 mutations, R133C and R306C cause the least severe clinical presentation, whereas the missense mutations R106W and T158M, and nonsense mutations R168X, R255X, R270X, and R294X cause the most severe phenotype. Large deletions in the MECP2 gene also cause a severe phenotype, whereas smaller C-terminal truncations are less severe. b Differences in XCI skewing patterns can influence clinical presentation, where patients with fewer cells expressing the mutant MECP2 gene will have less severe symptoms. c Individuals who have modifier mutations in genes that suppress the RTT phenotype have a more favorable clinical presentation than individuals with mutations in genes that enhance detrimental symptoms

Fig. 2

RTT patients and Mecp2-mutant mouse models share many features

Fig. 3

Treatment options in RTT either directly target MECP2 mutation or target pathways downstream of MECP2. Treatment options are further divided within these two groups

Fig. 4

Precision medicine for RTT. Different RTT patients will likely benefit from different combinations of treatment. When treating patients for RTT, their mutation status and XCI skewing should be taken into consideration. It is likely some patients will not be ideal candidates for gene therapy. Biomarkers, such as serum cholesterol, can be used to determine which patients will benefit from pharmacological intervention, such as statins. Management of other symptoms (seizures, scoliosis, lung infection, etc.) should also be considered. Together, RTT patients should receive individualized treatment to maximize their symptom improvement