Trends in Neurosciences
ReviewRett Syndrome: Crossing the Threshold to Clinical Translation
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)
Rett syndrome: from bed to bench
Pediatr. Neonatol.
(2011)Rett Syndrome: reaching for clinical trials
Neurotherapeutics
(2015)Rett syndrome treatment in mouse models: searching for effective targets and strategies
Neuropharmacology
(2013)- et al.
The story of Rett syndrome: from clinic to neurobiology
Neuron
(2007) Rett syndrome in Australia: a review of the epidemiology
J. Pediatr.
(2006)- et al.
Synaptic microcircuit dysfunction in genetic models of neurodevelopmental disorders: focus on Mecp2 and Met
Curr. Opin. Neurobiol.
(2011) Dendritic spine pathologies in hippocampal pyramidal neurons from Rett syndrome brain and after expression of Rett-associated MECP2 mutations
Neurobiol. Dis.
(2009)Astrocytes conspire with neurons during progression of neurological disease
Curr. Opin. Neurobiol.
(2012)NMDA receptor regulation prevents regression of visual cortical function in the absence of Mecp2
Neuron
(2012)- et al.
Synaptic circuit abnormalities of motor-frontal layer 2/3 pyramidal neurons in a mutant mouse model of Rett syndrome
Neurobiol. Dis.
(2010)