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Gene Therapy of the Central Nervous System. From Bench to Bedside. Book • 1st Edition • 9th May Authors: Michael G. Kaplitt and Matthew J. During.
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Fingolimod is able to increase BDNF expression and improved locomotor activity, sensorimotor coordination, and lifespan in RTT mice 71 , and a clinical trial ClinicalTrials. Glatiramer acetate, another BDNF secretion inducer, was first tested on a small cohort of patients with RTT, and an improvement of gait velocity was reported A second clinical trial had to be stopped because of a severe adverse effect on patients The IGF-1 full-length, also named mecasermin, was tested in three clinical studies 75 — A total of 10 patients with RTT treated in a preliminary week open-label assessment with mecasermin showed a reduction in the incidence of apneas and improvements of deleterious neurological consequences, including depression and anxiety However, a recent placebo-controlled crossover clinical trial on 30 patients with RTT did not succeed in confirming the improvements observed in the previous study After a pilot study investigating the safety of the IGF-1 tripeptide form 78 , a clinical trial with trofinetide an analogue of the IGF-1 tripeptide was recently published and presented improvements in core features of RTT Dextromethorphan, an NMDA receptor antagonist, has been tested for its capacity to restore normal EEG function and reduce seizure, and although no significant improvement in global severity was noticed, statistically significant changes were seen in clinical seizures, language, and behavioral hyperactivity Recent studies have suggested a systemic redox imbalance in a mouse model and in patients with RTT 82 — In two clinical trials, PUFA dietary supplementation was able to reduce oxidative stress markers and improve the biventricular myocardial systolic function 85 , The abovementioned clinical trials all originated from preclinical studies that identified promising therapeutic molecules.

In most cases, and as seen in preclinical studies, these treatments improved some RTT symptoms. However, one cannot help noticing that these therapeutic benefits are restricted to a sometimes small subset of symptoms. These last few years have been marked by a large improvement in innovative therapeutic strategies, such as gene therapy and gene editing. These new approaches are being applied to the RTT field and have already been the subject of a few publications. Unlike pharmacological approaches, these techniques are aimed at curing the disease rather than alleviating RTT symptoms, raising great hope for patients with RTT and their families.

However, these first publications also highlighted the need for increased safety, given the irrevocable nature of the proposed treatments. Since the gene responsible for RTT was identified almost 20 years ago 4 , a stupefying number of research projects aimed at understanding the mechanisms underlying this pathology and identifying potential therapeutic targets have been conducted. From these studies have stemmed many of the clinical trials whose results have recently been published. Even though many trials reported improvements, these were disappointingly small and restricted to a few symptoms at a time.

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This may be explained in part by the complex and often controversial functions of Mecp2 that have been unveiled throughout the years: The study of Mecp2 biology revealed an unexpected complexity, and this probably explains why Mecp2 replacement therapies such as gene therapy, gene editing, or X chromosome reactivation are now thought to be the best options to dramatically improve RTT or one day cure it. J-CR participated in conceptualizing, writing, reviewing, and editing the manuscript.

No competing interests were disclosed. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. F Faculty Reviews are commissioned from members of the prestigious F Faculty and are edited as a service to readers. In order to make these reviews as comprehensive and accessible as possible, the referees provide input before publication and only the final, revised version is published.

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If you still need help with your Google account password, please click here. If you still need help with your Facebook account password, please click here. We have sent an email to , please follow the instructions to reset your password. How to cite this article. Close Copy Citation Details. Rett syndrome from bench to bedside: Conceptualization, Writing — Original Draft Preparation. Mecp2 is known to play a role in chromatin organization and transcriptional regulation.

In this review, we report the latest advances on the molecular function of Mecp2 and the new animal and cellular models developed to better study Rett syndrome. Finally, we present the latest innovative therapeutic approaches, ranging from classical pharmacology to correct symptoms to more innovative approaches intended to cure the pathology. Keywords Rett syndrome, Mecp2, treatment. MECP2-pathies In addition to RTT, MECP2 mutations have been identified in individuals with syndromes such as mild learning disability in females, neonatal encephalopathy in males, and psychiatric disorders, autism spectrum disorders, and X-linked intellectual disability in both males and females 5.

Cell-specific expression of Mecp2 Mecp2 is widely expressed throughout the body and the highest abundance is in postmitotic neurons, where it contributes to the development and maintenance of synapses 8. Mecp2 binding and transcriptional regulation Mecp2 is a member of the methyl-CpG-binding domain MBD family of proteins 25 — 27 that are known to play a role in chromatin organization and transcriptional regulation through binding to methylated CpG sites or 5-hydroxymethylcytosine 28 , Preclinical models of Rett syndrome Several RTT mouse models have been developed and provided scientists with invaluable tools to understand the neurobiological mechanisms underlying RTT.

Therapeutic approaches Gene therapy As previously mentioned, RTT was shown to be fully reversible in a mouse model of the disease 52 , indicating that it could be amenable to gene therapy. X chromosome reactivation In female cells, one X chromosome is randomly inactivated and this ensures the same expression of X-linked genes in both male and female cells.

Clinical trials Since and the first clinical description of RTT, over 25 clinical trials testing therapeutic agents targeting motor, cognitive, and autonomous dysfunctions have been initiated. Conclusions Since the gene responsible for RTT was identified almost 20 years ago 4 , a stupefying number of research projects aimed at understanding the mechanisms underlying this pathology and identifying potential therapeutic targets have been conducted.

Competing interests No competing interests were disclosed. F recommended References 1. Review of Rett syndrome. J Neuropathol Exp Neurol.


Mild overexpression of MeCP2 causes a progressive neurological disorder in mice. Insight into Rett syndrome: MeCP2 levels display tissue- and cell-specific differences and correlate with neuronal maturation. Non-cell autonomous influence of MeCP2-deficient glia on neuronal dendritic morphology. MeCP2 is critical for maintaining mature neuronal networks and global brain anatomy during late stages of postnatal brain development and in the mature adult brain. Mutant astrocytes differentiated from Rett syndrome patients-specific iPSCs have adverse effects on wild-type neurons.

A role for glia in the progression of Rett's syndrome. Altered microtubule dynamics and vesicular transport in mouse and human MeCP2-deficient astrocytes. Conditional depletion of methyl-CpG-binding protein 2 in astrocytes depresses the hypercapnic ventilatory response in mice.

J Appl Physiol Impaired CO 2 sensitivity of astrocytes in a mouse model of Rett syndrome. Astrocytic modulation of excitatory synaptic signaling in a mouse model of Rett syndrome. Wild-type microglia arrest pathology in a mouse model of Rett syndrome. Wild-type microglia do not reverse pathology in mouse models of Rett syndrome. Influenza A induces dysfunctional immunity and death in MeCP2-overexpressing mice. Microglia contribute to circuit defects in Mecp2 null mice independent of microglia-specific loss of Mecp2 expression.

Oligodendrocyte lineage cells contribute unique features to Rett syndrome neuropathology. Purification, sequence, and cellular localization of a novel chromosomal protein that binds to methylated DNA. Genetic and physical mapping of a gene encoding a methyl CpG binding protein, Mecp2 , to the mouse X chromosome. MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system. Distribution, recognition and regulation of non-CpG methylation in the adult mammalian brain. Cell-type-specific repression by methyl-CpG-binding protein 2 is biased toward long genes. Disruption of DNA-methylation-dependent long gene repression in Rett syndrome.

MeCP2 recognizes cytosine methylated tri-nucleotide and di-nucleotide sequences to tune transcription in the mammalian brain. Radically truncated MeCP2 rescues Rett syndrome-like neurological defects.

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Characterization of Rett Syndrome-like phenotypes in Mecp2 -knockout rats. MeCP2 deficiency results in robust Rett-like behavioural and motor deficits in male and female rats. Int J Mol Sci. Neuronal cytoskeletal gene dysregulation and mechanical hypersensitivity in a rat model of Rett syndrome. Induction of pluripotent stem cells from fibroblast cultures. Differentiation of multipotent neural stem cells derived from Rett syndrome patients is biased toward the astrocytic lineage.

KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome. Reversal of neurological defects in a mouse model of Rett syndrome. Systemic delivery of MeCP2 rescues behavioral and cellular deficits in female mouse models of Rett syndrome. A codon-optimized Mecp2 transgene corrects breathing deficits and improves survival in a mouse model of Rett syndrome.

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Mol Ther Methods Clin Dev. Am J Hum Genet. Genetic and pharmacological reactivation of the mammalian inactive X chromosome. A mixed modality approach towards Xi reactivation for Rett syndrome and other X-linked disorders. Effect of Sarizotan, a 5-HT 1a and D2-like receptor agonist, on respiration in three mouse models of Rett syndrome.

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Treatment with desipramine improves breathing and survival in a mouse model for Rett syndrome. Pharmacological treatment with mirtazapine rescues cortical atrophy and respiratory deficits in MeCP2 null mice. Correction of respiratory disorders in a mouse model of Rett syndrome. Bdnf overexpression in hippocampal neurons prevents dendritic atrophy caused by Rett-associated MECP2 mutations. Li W, Pozzo-Miller L: BDNF deregulation in Rett syndrome.

Fingolimod, a sphingosine-1 phosphate receptor modulator, increases BDNF levels and improves symptoms of a mouse model of Rett syndrome. Expression of nuclear Methyl-CpG binding protein 2 Mecp2 is dependent on neuronal stimulation and application of Insulin-like growth factor 1. Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin recombinant human IGF-1 for the treatment of Rett syndrome. Placebo-controlled crossover assessment of mecasermin for the treatment of Rett syndrome.

Ann Clin Transl Neurol. Safety Assessment in Six Rett Patients. GABA and glutamate pathways are spatially and developmentally affected in the brain of Mecp2 -deficient mice. Randomized open-label trial of dextromethorphan in Rett syndrome. Oxidative burden and mitochondrial dysfunction in a mouse model of Rett syndrome.

Oxidative brain damage in Mecp2-mutant murine models of Rett syndrome. OxInflammation in Rett syndrome. Int J Biochem Cell Biol. Altered erythrocyte membrane fatty acid profile in typical Rett syndrome: Prostaglandins Leukot Essent Fatty Acids. Article Versions 1 version 1. This is an open access article distributed under the terms of the Creative Commons Attribution Licence , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Data associated with the article are available under the terms of the Creative Commons Zero "No rights reserved" data waiver CC0 1.

The NIH has approved more than gene therapy protocols since However, the field will require more research on gene delivery systems before gene therapy becomes an established therapeutic strategy for an array of central nervous system diseases. National Center for Biotechnology Information , U. Didn't get the message? Add to My Bibliography. Generate a file for use with external citation management software. Abstract The overall goal of this review is to provide the pediatric neurologist with a theoretical foundation in gene therapy.