Exposure –Response Efficacy Modeling to Support Trofinetide Dosing in Individuals with Rett Syndrome
ConclusionE –R efficacy modeling demonstrated significant relationships between trofinetide exposure and RSBQ, CSBS-DP-IT Social Composite, and RTT-COMC scores. Trofinetide is efficacious within the target exposure range, supporting the approved dosing regimen for trofinetide.Trial RegistrationNCT01703533, NCT02715115, NCT04181723. (Source: Advances in Therapy)
Source: Advances in Therapy - February 16, 2024 Category: Drugs & Pharmacology Source Type: research
MECP2-related disorders while gene-based therapies are on the horizon
The emergence of new genetic tools has led to the discovery of the genetic bases of many intellectual and developmental disabilities. This creates exciting opportunities for research and treatment development, and a few genetic disorders (e.g., spinal muscular atrophy) have recently been treated with gene-based therapies. MECP2 is found on the X chromosome and regulates the transcription of thousands of genes. Loss of MECP2 gene product leads to Rett Syndrome, a disease found primarily in females, and is characterized by developmental regression, motor dysfunction, midline hand stereotypies, autonomic nervous system dysfun...
Source: Frontiers in Genetics - February 12, 2024 Category: Genetics & Stem Cells Source Type: research
A Physiologically Based Pharmacokinetic Modeling Approach to Assess the Potential for Drug Interactions Between Trofinetide and CYP3A4-Metabolized Drugs
In this study that used a PBPK modeling approach, it was shown that CYP3A4 enzyme activity in the liver was not affected by trofinetide coadministration, but trofinetide was predicted to be a weak inhibitor of intestinal CYP3A4 metabolism after oral administration at therapeutic doses.PMID:38307724 | DOI:10.1016/j.clinthera.2023.12.007 (Source: Clinical Therapeutics)
Source: Clinical Therapeutics - February 2, 2024 Category: Drugs & Pharmacology Authors: Mona Darwish James M Youakim Inger Darling Viera Lukacova Joel S Owen Heather Bradley Source Type: research
Rett syndrome in Ireland: a demographic study
Rett syndrome (RTT) is a rare neurodevelopmental condition associated with mutations in the gene coding for the methyl-CpG-binding protein 2 (MECP2). It is primarily observed in girls and affects individuals glob... (Source: Orphanet Journal of Rare Diseases)
Source: Orphanet Journal of Rare Diseases - January 31, 2024 Category: Internal Medicine Authors: Komal Zade, Ciara Campbell, Snow Bach, Hazel Fernandes and Daniela Tropea Tags: Research Source Type: research
Gut microbes in central nervous system development and related disorders
The association between gut microbiota and central nervous system (CNS) development has garnered significant research attention in recent years. Evidence suggests bidirectional communication between the CNS and gut microbiota through the brain-gut axis. As a long and complex process, CNS development is highly susceptible to both endogenous and exogenous factors. The gut microbiota impacts the CNS by regulating neurogenesis, myelination, glial cell function, synaptic pruning, and blood-brain barrier permeability, with implication in various CNS disorders. This review outlines the relationship between gut microbiota and stag...
Source: Frontiers in Immunology - January 26, 2024 Category: Allergy & Immunology Source Type: research
Development of trofinetide for the treatment of Rett syndrome: from bench to bedside
Rett syndrome (RTT) is rare neurodevelopmental disorder caused by mutations in the MECP2 gene that encodes methyl-CpG-binding protein 2 (MeCP2), a DNA-binding protein with roles in epigenetic regulation of gene expression. Functional loss of MeCP2 results in abnormal neuronal maturation and plasticity, characterized by loss of verbal communication and loss of fine and gross motor function, among others. Trofinetide, a synthetic analog of glycine-proline-glutamate, was approved by the US Food and Drug Administration for the treatment of RTT in adult and pediatric patients aged 2 years and older. Here, we present the develo...
Source: Frontiers in Pharmacology - January 22, 2024 Category: Drugs & Pharmacology Source Type: research
POMC-specific knockdown of MeCP2 leads to adverse phenotypes in mice chronically exposed to high fat diet
Behav Brain Res. 2024 Mar 12;461:114863. doi: 10.1016/j.bbr.2024.114863. Epub 2024 Jan 13.ABSTRACTMethyl-CpG binding protein 2 (MeCP2) is an epigenetic factor associated with the neurodevelopmental disorders Rett Syndrome and MECP2 duplication syndrome. Previous studies have demonstrated that knocking out MeCP2 globally in the central nervous system leads to an obese phenotype and hyperphagia, however it is not clear if the hyperphagia is the result of an increased preference for food reward or due to an increase in motivation to obtain food reward. We show that mice deficient in MeCP2 specifically in pro-opiomelanocortin ...
Source: Behavioural Brain Research - January 15, 2024 Category: Neurology Authors: Priscila Frayre Karen Ponce-Rubio Jessica Frayre Jacquelin Medrano Elisa Sun Na Source Type: research
Sleep and the social profiles of individuals with Rett Syndrome
Individuals with Rett Syndrome (RTT) present unique social behaviors involving loss of spoken language, eye gaze communication, and gait abnormalities. In addition, sleeping is reported to be problematic. The aim of this study is to characterize social profiles in RTT and to examine their relationship with sleep, sleep-disordered breathing (SDB), and daytime sleepiness. (Source: Pediatric Neurology)
Source: Pediatric Neurology - January 8, 2024 Category: Neurology Authors: Xinyan ZHANG, Marcel SMITS, Leopold CURFS, Karen SPRUYT Tags: Research Paper Source Type: research
The Effect of Caregiver-Implemented Training on Augmentative Alternative Communication Use by Individuals with Rett Syndrome: Remote Coaching via Telehealth
. (Source: Developmental Neurorehabilitation)
Source: Developmental Neurorehabilitation - January 6, 2024 Category: Neurology Authors: Jennifer J. McComasRebecca KolbShawn GirtlerThe University of Minnesota, Minneapolis, MN, USA Source Type: research
Multilevel evidence of MECP2-associated mitochondrial dysfunction and its therapeutic implications
This study further supports the importance of the MECP2 gene in the mitochondrial pathways, which can open the gate for more personalized therapeutic interventions. Good cariprazine response highlights the role of dopamine dysfunction in the complex psychiatric symptoms of Rett syndrome. This can help identify the optimal treatment strategy from a transdiagnostic perspective instead of a classical diagnostic category. (Source: Frontiers in Psychiatry)
Source: Frontiers in Psychiatry - January 5, 2024 Category: Psychiatry Source Type: research
Therapeutic effects of extracorporeal shock wave therapy on patients with spastic cerebral palsy and Rett syndrome: clinical and ultrasonographic findings
Extracorporeal shock wave therapy (ESWT) is reportedly effective for improving spasticity and motor function in children with cerebral palsy (CP). Because late-stage Rett syndrome has a similar presentation, t... (Source: Orphanet Journal of Rare Diseases)
Source: Orphanet Journal of Rare Diseases - January 3, 2024 Category: Internal Medicine Authors: Ting-Yu Su, Yu-chi Huang, Jih-Yang Ko, Yi-Jung Hsin, Min-Yuan Yu and Pi-Lien Hung Tags: Research Source Type: research
An ambulatory dental treatment of a child with Rett syndrome and limited mouth opening under muscle relaxant-free general anesthesia: a case report
We report a child with RTT who received de... (Source: BMC Anesthesiology)
Source: BMC Anesthesiology - January 2, 2024 Category: Anesthesiology Authors: Xiao Tan, Bo Zhu, Yanchen Li and Yuguang Huang Tags: Case Report Source Type: research
Genetic Instability and Disease Progression of Indian Rett Syndrome Patients
AbstractRett syndrome (RTT) is the rare neurodevelopmental disorder caused by mutations in methyl CpG binding protein 2 (MECP2) gene with a prevalence of 1:10,000 worldwide. The hallmark clinical features of RTT are developmental delay, microcephaly, repetitive behaviours, gait abnormalities, respiratory abnormalities and seizures. Still, the understanding on the diagnosis of RTT among clinicians are less. The aim of our work was to study various clinical manifestations and a spectrum ofMECP2 genetic heterogeneity in RTT patients from South Indian population. We screened 208 autistic patients and diagnosed 20 RTT patients,...
Source: Molecular Neurobiology - December 26, 2023 Category: Neurology Source Type: research
Genes, Vol. 15, Pages 31: The Efficacy of a Human-Ready miniMECP2 Gene Therapy in a Pre-Clinical Model of Rett Syndrome
E. Sinnett
Inactivating mutations and the duplication of methyl-CpG binding protein 2 (MeCP2), respectively, mediate Rett syndrome (RTT) and MECP2 duplication syndrome. These disorders underscore the conceptual dose-dependent risk posed by MECP2 gene therapy for mosaic RTT patients. Recently, a miRNA-Responsive Autoregulatory Element (miRARE) mitigated the dose-dependent toxicity posed by self-complementary adeno-associated viral vector serotype 9 (AAV9) miniMECP2 gene therapy (scAAV9/miniMECP2-myc) in mice. Here, we report an efficacy assessment for the human-ready version of this regulated gene therapy (TSHA-102) in...
Source: Genes - December 24, 2023 Category: Genetics & Stem Cells Authors: Chanchal Sadhu Christopher Lyons Jiyoung Oh Indumathy Jagadeeswaran Steven J. Gray Sarah E. Sinnett Tags: Article Source Type: research
