Rare Diseases Report 2022

Rett syndrome: Looking to the future and the promise of gene therapy


The dream of curing genetic disorders has been a persistent but elusive goal, even before the human genome was mapped. Once mapping of the human genome was complete in 2001, an entirely new avenue of potential treatments and cures for genetic diseases and disorders was opened.1,2

Courtney S. Ambrose is a student in the master's of science in human genetics and genomic data analytics program at Keck Graduate Institute, Claremont, Calif.

Courtney S. Ambrose

The disorders best suited for targeted gene therapy are monogenic; however, tools and delivery methods for editing the human genome were limited and difficult to apply, until the advent of the CRISPR system in 2012.3 CRISPR (an acronym of clustered regularly interspaced short palindromic repeats) has changed the way in which gene therapy strategies are pursued, with dozens of companies leveraging a variety of platforms to create potentially life-changing therapies for devastating rare diseases and disorders.

One of the rare monogenic disorders that is embracing multiple gene therapy approaches is Rett syndrome, a rare, debilitating neurodevelopmental disorder. In this review, we explore the molecular cause of Rett syndrome, disease presentation, current treatments, ongoing clinical trials, and therapies that are on the horizon.

Underlying molecular cause

Rett syndrome is caused by mutations in, or the absence of, the MECP2 gene, which produces methyl-CpG binding protein 2 (MECP2). The syndrome was first described clinically in 1954 by the Austrian physician Andreas Rett; it would take until 1982 before the disorder was officially named, eponymously, in a seminal paper by Hagberg.4 After Hagberg’s characterization, Rett syndrome became the predominant global clinical diagnosis identified among cognitively impaired females, with an incidence of 1 in every 10,000 to 15,000.4

Barbara J. Bailus, PhD, is an assistant professor of genetics at Keck Graduate Institute, Claremont, Calif.

Dr. Barbara J. Bailus

In 1999, mutations in, and deletions of, MECP2 were identified as the cause of Rett syndrome.4,5 MECP2 is located on the X chromosome, in the Xq28 region, making Rett syndrome an X-linked dominant disorder.6 Rett syndrome is seen predominantly in females who are mosaic for mutant or deleted MECP2. Random X chromosome inactivation results in some cells expressing the mutant MECP2 allele and other cells expressing the normal functioning MECP2 allele; the percentage of cells expressing the normal allele correlates with the degree of syndrome severity.7-9

The incidence of Rett syndrome is much lower in males, in whom the syndrome was originally thought to be lethal; many observed male cases are either mosaic or occur in XXY males.10,11

Approximately 95% of cases of Rett syndrome are due to de novo mutations in MECP2, with a handful of specific mutations and large deletions accounting for more than 85% of cases.12 The fact that Rett syndrome is monogenic and most cases are caused by, in total, only a handful of mutations or deletions makes the syndrome a promising candidate for gene therapy.

At the molecular level, it has been observed that the MECP2 mutations of Rett syndrome lead to loss of gene function, thus disrupting the ability of the MECP2 nuclear protein to regulate global gene transcription through its binding to methylated DNA sites.12 A large percentage of these missense and nonsense mutations lead to a truncated or nonfunctional protein.12

One of the ways in which MECP2 regulates transcription is as a component of heterochromatin condensates and by separation of heterochromatin and euchromatin.13-15 It has been observed that the cells of Rett syndrome patients have an altered chromatin state, potentially contributing to transcriptional dysregulation.16,17 Several mutations observed in Rett syndrome patients occur in crucial domains for heterochromatin condensate formation, which helps explain this cellular phenotype.13 Introduction of a engineered “mini” MECP2 in a murine model of Rett syndrome has resulted in partial rescue of heterochromatin condensate formation and transcriptional regulation – fostering the hypothesis that correcting those genetic changes could lead to a potential therapy.18

Beyond the role of MECP2 in heterochromatin condensate formation, the gene interacts with more than 40 proteins that have diverse roles in cellular function, epigenetic modulation, and neuronal development. This volume of interactions contributes to MECP2 being a global gene regulatory protein that has far-reaching effects on transcriptional regulation across the genome.19-22

Epigenetic dysregulation has been associated with neurodevelopmental and neuropsychiatric disorders.23 Both insulin-like growth factor 1 (IGF-1) and brain-derived neurotrophic factor are transcriptional targets of MECP2, and are involved in neuronal differentiation, synaptic function, and neurite outgrowth.12 This helps explain the neurodevelopmental phenotypes observed in MECP2-mutated patients.

Notably, although Rett syndrome patients experience neurodevelopmental phenotypes at the cellular level, neuronal death is not readily observed. That observation provides hope that an interventional therapy after onset of symptoms might still be of benefit.


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