Trends in Neurosciences
Volume 39, Issue 2, February 2016, Pages 100-113
Journal home page for Trends in Neurosciences

Review
Rett Syndrome: Crossing the Threshold to Clinical Translation

https://doi.org/10.1016/j.tins.2015.12.008Get rights and content

Trends

Studies of RTT mouse models have convincingly demonstrated that neurological disability caused by loss of methyl-CpG-binding protein 2 (MeCP2) function is reversible to a significant degree.

Recent insights into the biology of MeCP2 and its role in regulating interactions between DNA and repressor protein complexes seemed poised to resolve longstanding controversies about the role of MeCP2 in transcriptional control.

The knowledge that reintroduction of Mecp2 can restore circuit functionality in mouse models of RTT has spurred the investigation of gene replacement and gene reactivation strategies as comprehensive and potentially transformative treatment approaches for RTT.

Pharmacologic strategies targeting neurotransmitter and neuronal growth factor signaling pathways have proven highly effective at improving neurological function in mouse models of RTT.

The natural history of RTT is becoming increasingly well defined, facilitating the identification of clinically measurable endpoints for therapeutic trials.

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.

Section snippets

Progress in Identifying Potential RTT Therapeutics

RTT is a severe neurodevelopmental disorder resulting from mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2) [1]. Progress in understanding the pathophysiology of RTT and in identifying potential therapies has outpaced that in many other neurodevelopmental disorders due, in part, to the availability of rodent models with good construct and face validity 2, 3, 4. These include strains of mice carrying either Mecp2-null or hypomorphic alleles or human disease-causing

Genetics and Clinical Features of RTT

The MECP2 gene is X linked and RTT mutations arise predominantly in the paternal germ line. Given that the gene is subject to X chromosome inactivation, most affected individuals are female heterozygotes who are somatic mosaics for normal and mutant MECP2. In rare cases, males can be born with an MECP2 mutation derived from the mother who either has favorable X chromosome inactivation patterns or gonadal mosaicism. However, because males have only one X chromosome, many such individuals are

Neural Circuit Defects Resulting from Loss of MeCP2

Despite ongoing questions about the normal function of MeCP2, the effects of MeCP2 deficiency on many aspects of brain structure and function are now clear. Histopathological evidence from patients with RTT and Mecp2 mutant mice shows that loss of MeCP2 does not result in neuronal cell death, axonal degeneration, or other irreversible deficits [17], consistent with the finding that neurological dysfunction in conditional Mecp2 mutants is largely reversible upon reactivation of silent Mecp2

Gene Dosage Concerns

The ultimate goal of strategies that target MECP2 directly would be to normalize expression without affecting the levels of other genes. However, these treatment approaches must carefully consider the consequences of MeCP2 dosage. An excess of MeCP2 in both humans and mice impairs neuronal development and causes severe neurological dysfunction. For example, mice overexpressing MeCP2 display seizures and hypoactivity 42, 43, and boys with MECP2 duplication syndrome exhibit some phenotypes that

Therapeutic Targets Downstream of MECP2

By using clinically relevant outcome measures, preclinical studies of potential RTT therapeutics have, in a relatively short period of time, produced compelling evidence that signaling pathways well downstream of Mecp2 can be effectively targeted to ameliorate specific disease symptoms. In general, the pathways that have been targeted fall into three categories: (i) classical neurotransmitter and neuromodulator systems, including noradrenergic, serotonergic, glutamatergic, GABAergic, and

The United States RTT Natural History Study

Clinical trials in rare diseases are confounded by the limited, often heterogeneous, pool of affected individuals, and difficulty selecting endpoints with a large effect size 71, 72, 73, 74, 75. However, observational natural-history studies have been useful to understand the range of manifestations and progression of other rare diseases, and to establish valid and reliable short-term and long-term outcome measures or biomarkers 76, 77. Therefore, the United States RTT Natural History Study

Concluding Remarks and Future Directions

This is a promising time for the RTT field as researchers move closer to understanding the basic biology of MeCP2 and there are more and more examples of interventions that improve or reverse symptoms in mouse models. By definition, therefore, this is also a time for caution, because the expectations of families affected by RTT must be managed appropriately (see Outstanding Questions). Based on a wealth of experience with other disorders, the chance that any particular treatment will translate

Acknowledgments

This work was supported by grants awarded to D.M.K. from NINDS (RO1NS057398) and the Rett Syndrome Research Trust (RSRT); to A.B. from The Wellcome Trust (grants 091580 and 092076) and RSRT; to B.D.P. from the Simons Foundation (SFARI Award 274426), NINDS (R01NS085093), NIMH (R01MH093372), and RSRT; to S.J.G. from Rettsyndrome.org, RSRT and Research to Prevent Blindness through the UNC Department of Ophthalmology; to D.U.M. from NICHD (RO1HD036655; T. Magnuson, PI). The authors thank Dr. James

References (124)

  • H. Van Esch

    Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males

    Am. J. Hum. Genet.

    (2005)
  • D. del Gaudio

    Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males

    Genet. Med.

    (2006)
  • B.H. Yeung

    Evolution and roles of stanniocalcin

    Mol. Cell. Endocrinol.

    (2012)
  • S.J. Gray

    Preclinical differences of intravascular AAV9 delivery to neurons and glia: a comparative study of adult mice and nonhuman primates

    Mol. Ther.

    (2011)
  • S. Duque

    Intravenous administration of self-complementary AAV9 enables transgene delivery to adult motor neurons

    Mol. Ther.

    (2009)
  • K.K. Gadalla

    Improved survival and reduced phenotypic severity following AAV9/MECP2 gene transfer to neonatal and juvenile male Mecp2 knockout mice

    Mol. Ther.

    (2013)
  • J.M. Ramirez

    Breathing challenges in Rett Syndrome: lessons learned from humans and animal models

    Respir. Physiol. Neurobiol.

    (2013)
  • D.M. Katz

    Breathing disorders in Rett syndrome: progressive neurochemical dysfunction in the respiratory network after birth

    Respir. Physiol. Neurobiol.

    (2009)
  • J.M. Dwyer et al.

    Activation of mammalian target of rapamycin and synaptogenesis: role in the actions of rapid-acting antidepressants

    Biol. Psychiatry

    (2013)
  • J. Bogaerts

    Clinical trial designs for rare diseases: studies developed and discussed by the International Rare Cancers Initiative

    Eur. J. Cancer

    (2015)
  • C. Tudur Smith

    Methodology of clinical trials for rare diseases

    Best Pract. Res. Clin. Rheumatol.

    (2014)
  • J.H. van der Lee

    Efficient ways exist to obtain the optimal sample size in clinical trials in rare diseases

    J. Clin. Epidemiol.

    (2008)
  • P. Bauer et al.

    The advantages and disadvantages of adaptive designs for clinical trials

    Drug Discov. Today

    (2004)
  • Y. Blat et al.

    Drug discovery of therapies for Duchenne muscular dystrophy

    J. Biomol. Screen.

    (2015)
  • E. Monros

    Rett syndrome in Spain: mutation analysis and clinical correlations

    Brain Dev.

    (2001)
  • J.D. Lewis

    Purification, sequence and cellular localisation of a novel chromosomal protein that binds to methylated DNA

    Cell

    (1992)
  • P.J. Skene

    Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state

    Mol. Cell

    (2010)
  • T. Baubec

    Methylation-dependent and -independent genomic targeting principles of the MBD protein family

    Cell

    (2013)
  • R.E. Amir

    Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2

    Nat. Genet.

    (1999)
  • D.M. Katz

    Preclinical research in Rett syndrome: setting the foundation for translational success

    Dis. Model. Mech.

    (2012)
  • K.K. Gadalla

    MeCP2 and Rett syndrome: reversibility and potential avenues for therapy

    Biochem. J.

    (2011)
  • L.M. Lombardi

    MECP2 disorders: from the clinic to mice and back

    J. Clin. Invest.

    (2015)
  • C.A. Chapleau

    Recent progress in Rett Syndrome and MeCP2 dysfunction: assessment of potential treatment options

    Future Neurol.

    (2013)
  • J.L. Neul

    Specific mutations in methyl-CpG-binding protein 2 confer different severity in Rett syndrome

    Neurology

    (2008)
  • B. Hagberg

    Clinical manifestations and stages of Rett syndrome

    Ment. Retard. Dev. Disabil. Res. Rev.

    (2002)
  • J.L. Neul

    The relationship of Rett syndrome and MECP2 disorders to autism

    Dialogues Clin. Neurosci.

    (2012)
  • A. Rett

    [On a unusual brain atrophy syndrome in hyperammonemia in childhood]

    Wien. Med. Wochenschr.

    (1966)
  • J.L. Neul

    Developmental delay in Rett syndrome: data from the natural history study

    J. Neurodev. Disord.

    (2014)
  • H. Wandin

    Communication intervention in Rett syndrome: a survey of speech language pathologists in Swedish health services

    Disabil. Rehabil.

    (2015)
  • S. Akbarian

    The neurobiology of Rett syndrome

    Neuroscientist

    (2003)
  • J. Guy

    Reversal of neurological defects in a mouse model of Rett syndrome

    Science

    (2007)
  • D.D. Armstrong

    Neuropathology of Rett syndrome

    J. Child Neurol.

    (2005)
  • R.C. Samaco

    Loss of MeCP2 in aminergic neurons causes cell-autonomous defects in neurotransmitter synthesis and specific behavioral abnormalities

    Proc. Natl. Acad. Sci. U.S.A.

    (2009)
  • M.V. Johnston

    Neurobiology of Rett syndrome

    Neuropediatrics

    (1995)
  • M.E. Blue

    Development of amino acid receptors in frontal cortex from girls with Rett syndrome

    Ann. Neurol.

    (1999)
  • G.L. Wenk

    Altered neurochemical markers in Rett's syndrome

    Neurology

    (1991)
  • S. Cohen et al.

    Communication between the synapse and the nucleus in neuronal development, plasticity, and disease

    Annu. Rev. Cell Dev. Biol.

    (2008)
  • H. Cheval

    Postnatal inactivation reveals enhanced requirement for MeCP2 at distinct age windows

    Hum. Mol. Genet.

    (2012)
  • C.M. McGraw

    Adult neural function requires MeCP2

    Science

    (2011)
  • M.P. Blackman

    A critical and cell-autonomous role for MeCP2 in synaptic scaling up

    J. Neurosci.

    (2012)
  • Cited by (0)

    View full text