Probing a neural unreliability account of auditory sensory processing atypicalities in Rett Syndrome.

BACKGROUND: In the search for objective tools to quantify neural function in Rett Syndrome (RTT), which are crucial in the evaluation of therapeutic efficacy in clinical trials, recordings of sensory-perceptual functioning using event-related potential (ERP) approaches have emerged as potentially powerful tools. Considerable work points to highly anomalous auditory evoked potentials (AEPs) in RTT. However, an assumption of the typical signal-averaging method used to derive these measures is "stationarity" of the underlying responses - i.e. neural responses to each input are highly stereotyped. An alternate possibility is that responses to repeated stimuli are highly variable in RTT. If so, this will significantly impact the validity of assumptions about underlying neural dysfunction, and likely lead to overestimation of underlying neuropathology. To assess this possibility, analyses at the single-trial level assessing signal-to-noise ratios (SNR), inter-trial variability (ITV) and inter-trial phase coherence (ITPC) are necessary. METHODS: AEPs were recorded to simple 100 Hz tones from 18 RTT and 27 age-matched controls (Ages: 6-22 years). We applied standard AEP averaging, as well as measures of neuronal reliability at the single-trial level (i.e. SNR, ITV, ITPC). To separate signal-carrying components from non-neural noise sources, we also applied a denoising source separation (DSS) algorithm and then repeated the reliability measures. RESULTS: Substantially increased ITV, lower SNRs, and reduced ITPC were observed in auditory responses of RTT participants, supporting a "neural unreliability" account. Application of the DSS technique made it clear that non-neural noise sources contribute to overestimation of the extent of processing deficits in RTT. Post-DSS, ITV measures were substantially reduced, so much so that pre-DSS ITV differences between RTT and TD populations were no longer detected. In the case of SNR and ITPC, DSS substantially improved these estimates in the RTT population, but robust differences between RTT and TD were still fully evident. CONCLUSIONS: To accurately represent the degree of neural dysfunction in RTT using the ERP technique, a consideration of response reliability at the single-trial level is highly advised. Non-neural sources of noise lead to overestimation of the degree of pathological processing in RTT, and denoising source separation techniques during signal processing substantially ameliorate this issue.

A small-molecule TrkB ligand improves dendritic spine phenotypes and atypical behaviors in female Rett syndrome mice.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in MECP2, which encodes methyl-CpG-binding protein 2, a transcriptional regulator of many genes, including brain-derived neurotrophic factor (BDNF). BDNF levels are lower in multiple brain regions of Mecp2-deficient mice, and experimentally increasing BDNF levels improve atypical phenotypes in Mecp2 mutant mice. Due to the low blood-brain barrier permeability of BDNF itself, we tested the effects of LM22A-4, a brain-penetrant, small-molecule ligand of the BDNF receptor TrkB (encoded by Ntrk2), on dendritic spine density and form in hippocampal pyramidal neurons and on behavioral phenotypes in female Mecp2 heterozygous (HET) mice. A 4-week systemic treatment of Mecp2 HET mice with LM22A-4 restored spine volume in MeCP2-expressing neurons to wild-type (WT) levels, whereas spine volume in MeCP2-lacking neurons remained comparable to that in neurons from female WT mice. Female Mecp2 HET mice engaged in aggressive behaviors more than WT mice, the levels of which were reduced to WT levels by the 4-week LM22A-4 treatment. These data provide additional support to the potential usefulness of novel therapies not only for RTT but also to other BDNF-related disorders.

Normalized Clinical Severity Scores Reveal a Correlation between X Chromosome Inactivation and Disease Severity in Rett Syndrome.

Rett Syndrome (RTT) is a severe neurodevelopmental disorder predominately diagnosed in females and primarily caused by pathogenic variants in the X-linked gene Methyl-CpG Binding Protein 2 (MECP2). Most often, the disease causing the MECP2 allele resides on the paternal X chromosome while a healthy copy is maintained on the maternal X chromosome with inactivation (XCI), resulting in mosaic expression of one allele in each cell. Preferential inactivation of the paternal X chromosome is theorized to result in reduced disease severity; however, establishing such a correlation is complicated by known MECP2 genotype effects and an age-dependent increase in severity. To mitigate these confounding factors, we developed an age- and genotype-normalized measure of RTT severity by modeling longitudinal data collected in the US Rett Syndrome Natural History Study. This model accurately reflected individual increase in severity with age and preserved group-level genotype specific differences in severity, allowing for the creation of a normalized clinical severity score. Applying this normalized score to a RTT XCI dataset revealed that XCI influence on disease severity depends on MECP2 genotype with a correlation between XCI and severity observed only in individuals with MECP2 variants associated with increased clinical severity. This normalized measure of RTT severity provides the opportunity for future discovery of additional factors contributing to disease severity that may be masked by age and genotype effects.

Generation of human induced pluripotent stem cell lines derived from four Rett syndrome patients with MECP2 mutations.

Rett syndrome is characterized by severe global developmental impairments with autistic features and loss of purposeful hand skills. Here we show that human induced pluripotent stem cell (hiPSC) lines derived from four Japanese female patients with Rett syndrome are generated from peripheral blood mononuclear cells using Sendai virus vectors. The generated hiPSC lines showed self-renewal and pluripotency and carried heterozygous frameshift, missense, or nonsense mutations in the MECP2 gene. Since the molecular pathogenesis caused by MECP2 dysfunction remains unclear, these cell resources are useful tools to establish disease models and develop new therapies for Rett syndrome.

[Preimplantation genetic testing for a Chinese pedigree affected with Rett syndrome].

OBJECTIVE: To carry out preimplantation genetic testing (PGT) for a Chinese pedigree affected with Rett syndrome (RTT). METHODS: A pedigree affected with RTT who had presented at the First Hospital of Jilin University on June 4, 2021 was selected as the study subject. Variant of the MECP2 gene was analyzed by next generation sequencing (NGS) and Sanger sequencing. Direct sequencing was also used to determine the carrier status for the c.925C>T variant of the MECP2 gene in the blastocysts, and Sanger sequencing was used to validate the results. The MECP2 gene and 168 effective single nucleotide polymorphism (SNP) loci within 2 Mb ranges up- and downstream of the gene were used to construct a haplotype for analyzing the variant site in the embryos, and embryos without the variant were subjected to the analysis for chromosomal aneuploidies. RESULTS: PGT analysis revealed that five out of seven blastocysts did not harbor the pathogenic variant. The results of aneuploidy analysis indicated that two out of five blastocysts without the variant were euploid. Following genetic counselling, the couple had opted to transplant the optimal blastocyst. Following clinical pregnancy, prenatal diagnosis showed that the fetus has a normal chromosomal karyotype, and the c.925C>T variant was not detected in the amniotic fluid sample. A healthy girl was born by Cesarean section at full term. CONCLUSION: NGS can attain efficient PGT detection and reduce the risk of disease recurrence in families affected with RTT.

Use of a low-tech tool in the improvement of social interaction of patients with Rett Syndrome: an observational study.

Introduction: The main aim of the present study was to examine whether the use of a low-tech tool, called click4all, inserted into cognitive and motor training can increase social interaction of patients with Rett Syndrome (RTT) with classmates in a school setting. Methods: Twenty-seven participants with RTT were randomly assigned to two groups: the experimental group received treatment with click4all, and the control group received traditional treatment without click4all. Parameters were measured before treatment (T1), 6 months after treatment (T2), 6 months after the second treatment phase (T3) and at the end of the third treatment phase (T4). Results: The results demonstrated an increase in levels of social interaction among classmates and patients with RTT in the experimental group, over time, compared to the control group, 95% CI [5.20-15.30]. Classmates also showed a higher level of knowledge related to participants of the experimental group, and this increased over time, 95% CI [24.98-63.52]. The level of knowledge related to the control group was stable over time and lower than the experimental group. Discussion: This study demonstrated that the use of a low-tech tool can increase social interactions of patients with RTT in a school setting. This is important, as patients with RTT are often restricted in an isolation condition.

Metformin Induces MeCP2 in the Hippocampus of Male Mice with Sex-Specific and Brain-Region-Dependent Molecular Impact.

Rett Syndrome (RTT) is a progressive X-linked neurodevelopmental disorder with no cure. RTT patients show disease-associated symptoms within 18 months of age that include developmental regression, progressive loss of useful hand movements, and breathing difficulties, along with neurological impairments, seizures, tremor, and mental disability. Rett Syndrome is also associated with metabolic abnormalities, and the anti-diabetic drug metformin is suggested to be a potential drug of choice with low or no side-effects. Previously, we showed that in vitro exposure of metformin in a human brain cell line induces MECP2E1 transcripts, the dominant isoform of the MECP2 gene in the brain, mutations in which causes RTT. Here, we report the molecular impact of metformin in mice. Protein analysis of specific brain regions in the male and female mice by immunoblotting indicated that metformin induces MeCP2 in the hippocampus, in a sex-dependent manner. Additional experiments confirm that the regulatory role of metformin on the MeCP2 target "BDNF" is brain region-dependent and sex-specific. Measurement of the ribosomal protein S6 (in both phosphorylated and unphosphorylated forms) confirms the sex-dependent role of metformin in the liver. Our results can help foster a better understanding of the molecular impact of metformin in different brain regions of male and female adult mice, while providing some insight towards its potential in therapeutic strategies for the treatment of Rett Syndrome.

Emerging therapies for childhood-onset movement disorders.

PURPOSE OF REVIEW: We highlight novel and emerging therapies in the treatment of childhood-onset movement disorders. We structured this review by therapeutic entity (small molecule drugs, RNA-targeted therapeutics, gene replacement therapy, and neuromodulation), recognizing that there are two main approaches to treatment: symptomatic (based on phenomenology) and molecular mechanism-based therapy or 'precision medicine' (which is disease-modifying). RECENT FINDINGS: We highlight reports of new small molecule drugs for Tourette syndrome, Friedreich's ataxia and Rett syndrome. We also discuss developments in gene therapy for aromatic l-amino acid decarboxylase deficiency and hereditary spastic paraplegia, as well as current work exploring optimization of deep brain stimulation and lesioning with focused ultrasound. SUMMARY: Childhood-onset movement disorders have traditionally been treated symptomatically based on phenomenology, but focus has recently shifted toward targeted molecular mechanism-based therapeutics. The development of precision therapies is driven by increasing capabilities for genetic testing and a better delineation of the underlying disease mechanisms. We highlight novel and exciting approaches to the treatment of genetic childhood-onset movement disorders while also discussing general challenges in therapy development for rare diseases. We provide a framework for molecular mechanism-based treatment approaches, a summary of specific treatments for various movement disorders, and a clinical trial readiness framework.

[Clinical and molecular genetic analysis of a child with comorbid 16p11.2 microdeletion syndrome and Rett syndrome].

OBJECTIVE: To explore the genetic characteristics of a child with comorbid 16p11.2 microdeletion syndrome and Rett syndrome (RTT). METHODS: A male infant who was admitted to Gansu Provincial Maternity and Child Health Care Hospital in May 2020 was selected as the study subject. Clinical data of the infant was collected. Genomic DNA was extracted from peripheral blood samples from the infant and his parents, and subjected to whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing. RESULTS: The patient, a 4-day-old male infant, had presented with poor response, poor intake, feeding difficulties, and deceased at 8 months after birth. WES revealed that he has harbored a 0.643 Mb deletion in the 16p11.2 region, which encompassed key genes of the 16p11.2 microdeletion syndrome such as ALDOA, CORO1A, KIFF22, PRRT2 and TBX6. His father has carried the same deletion, but was phenotypically normal. The deletion was predicted to be pathogenic. The child was also found to harbor a maternally derived c.763C>T (p.R255X) hemizygous variant of the MECP2 gene, which was also predicted to be pathogenic (PVS1+PS4+PM2_Supporting). CONCLUSION: The 16p11.2 deletion and the MECP2: c.763C>T (p.R255X) variant probably underlay the pathogenesis in this infant.

Prevalence of Endocrinopathies in a Cohort of Patients with Rett Syndrome: A Two-Center Observational Study.

Systematic data on endocrinopathies in Rett syndrome (RTT) patients remain limited and inconclusive. The aim of this retrospective observational two-center study was to assess the prevalence of endocrinopathies in a pediatric population of RTT patients. A total of 51 Caucasian patients (47 girls, 4 boys) with a genetically confirmed diagnosis of RTT were enrolled (mean age 9.65 ± 5.9 years). The patients were referred from the Rett Center of two Italian Hospitals for endocrinological evaluation. All the study population underwent clinical and auxological assessments and hormonal workups. MeCP2 mutations were detected in 38 cases (74.5%), CDKL5 deletions in 11 (21.6%), and FOXG1 mutations in 2 (3.9%). Overall, 40 patients were treated with anti-seizure medications. The most frequent endocrinological finding was short stature (47%), followed by menstrual cycle abnormalities (46.2%), weight disorders (45.1%), low bone mineral density (19.6%), hyperprolactinemia (13.7%) and thyroid disorders (9.8%). In the entire study population, endocrinopathies were significantly more frequent in patients with MeCP2 mutations (p = 0.0005), and epilepsy was more frequent in CDKL5 deletions (p = 0.02). In conclusion, our data highlighted that endocrinopathies are not rare in RTT, especially in patients with MeCP2 deletions. Therefore, in the context of a multidisciplinary approach, endocrinological evaluation should be recommended for RTT patients.

Safety and efficacy of trofinetide in Rett syndrome: a systematic review and meta-analysis of randomized controlled trials.

INTRODUCTION: Rett syndrome is a rare genetic neurodevelopmental disorder that predominantly impacts females. It presents with loss of acquired skills, impaired communication, and stereotypic hand movements. Given the limited treatment options for Rett syndrome, there is a dire need for effective interventions. OBJECTIVE: To evaluate the safety and efficacy of trofinetide in Randomized Controlled Trials (RCTs) that report on Rett syndrome patients. METHODS: We identified 109 articles from four databases (Scopus, PubMed, Web of Science, and Cochrane CENTRAL). After removing the duplicates, we narrowed them down to 59 articles for further assessment. We included RCTs that evaluated the efficacy and safety of trofinetide in patients with Rett syndrome. Three studies were eligible for inclusion. Two independent reviewers evaluated the identified studies' titles, abstracts, and full texts, extracting pertinent data. We assessed the quality of the studies using the Cochrane Risk of Bias (RoB) 2.0 tool. We then conducted a meta-analysis using the fixed effects model in the case of insignificant heterogeneity; otherwise, we used the random effects model. Based on the nature of the outcome, we analyzed the mean difference or the odds ratio. Analysis was conducted using RevMan version 5.3. RESULTS: Among the analyzed outcomes in 181 patients in the trofinetide group and 134 patients in the placebo group, significant improvement in Rett Syndrome Behavior Questionnaire (RSBQ) scores was observed at 200 mg dosage (overall mean difference: -3.53, p = 0.001). Clinical Global Impression-Improvement (CGI-I) scores improved considerably at 200 mg dosage (overall mean difference: -0.34, p < 0.0001). No substantial changes were observed in Motor Behavioral Assessment (MBA) or Top 3 Caregiver Concerns. We evaluated Treatment Emergent Adverse Events (TEAEs) across the various dosages and noted significant associations with diarrhea (200 mg), vomiting (200 mg), and irritability (200 mg). However, we did not find a significant association between any of the dosages and the incidence of decreased appetite. CONCLUSION: Trofinetide demonstrated potential in improving RSBQ and CGI-I scores at 200 mg dosage. Although no substantial changes were found in MBA and top 3 caregiver concerns. Adverse events were linked to specific dosages.

Adolescents with Rett syndrome at critical care pathway junctures: Examining clinicians' decision to initiate invasive long-term ventilation.

BACKGROUND: The initiation of invasive long-term ventilation (I-LTV) for an adolescent with Rett Syndrome (RTT) involves many serious bioethical considerations. In moving towards a more inclusive model of patient participation, transparency surrounding the main influencing factors around this decision is important. OBJECTIVE: We aimed to identify the main drivers influencing a clinician's decision to support initiation of I-LTV for an adolescent with RTT. METHOD: We used an anonymous online vignette-based factorial survey. The survey was distributed internationally through eight professional multi-disciplinary organisations to reach clinicians working in paediatrics. RESULTS: We analysed 504 RTT vignettes completed by 246 clinicians using mixed effect regression modelling. The main three significant influencing factors identified were: parental agreement with the decision to support initiation, the family's support network, and proximity to a tertiary care centre. Additional comments from participants focused on family support, and the importance of on-going communication with the family. CONCLUSION: As the rights of those with disabilities improve and participation of adolescents in decision-making becomes more established, effective communications with the family around goals of care and particular sensitivity and reflective practice around methods of consensus building will likely contribute to a positive decision-making process at this difficult time.

Sensory experiences questionnaire unravels differences in sensory profiles between MECP2-related disorders.

The methyl CpG-binding protein-2 (MECP2) gene is located on the Xq28 region. Loss of function mutations or increased copies of MECP2 result in Rett syndrome (RTT) and MECP2 duplication syndrome (MDS), respectively. Individuals with both disorders exhibit overlapping autism symptoms, yet few studies have dissected the differences between these gene dosage sensitive disorders. Further, research examining sensory processing patterns in persons with RTT and MDS is largely absent. Thus, the goal of this study was to analyze and compare sensory processing patterns in persons with RTT and MDS. Towards this goal, caregivers of 50 female individuals with RTT and 122 male individuals with MDS, between 1 and 46 years of age, completed a standardized measure of sensory processing, the Sensory Experiences Questionnaire. Patterns detected in both disorders were compared against each other and against normative values. We found sensory processing abnormalities for both hyper- and hypo-sensitivity in both groups. Interestingly, abnormalities in MDS were more pronounced compared with in RTT, particularly with items concerning hypersensitivity and sensory seeking, but not hyposensitivity. Individuals with MDS also exhibited greater sensory symptoms compared with RTT in the areas of tactile and vestibular sensory processing and for both social and nonsocial stimuli. This study provides a first description of sensory symptoms in individuals with RTT and individuals with MDS. Similar to other neurodevelopmental disorders, a variety of sensory processing abnormalities was found. These findings reveal a first insight into sensory processing abnormalities caused by a dosage sensitive gene and may ultimately help guide therapeutic approaches for these disorders.

Systematic and quantitative analysis of stop codon readthrough in Rett syndrome nonsense mutations.

Rett syndrome (RTT) is a neurodevelopmental disorder resulting from genetic mutations in the methyl CpG binding protein 2 (MeCP2) gene. Specifically, around 35% of RTT patients harbor premature termination codons (PTCs) within the MeCP2 gene due to nonsense mutations. A promising therapeutic avenue for these individuals involves the use of aminoglycosides, which stimulate translational readthrough (TR) by causing stop codons to be interpreted as sense codons. However, the effectiveness of this treatment depends on several factors, including the type of stop codon and the surrounding nucleotides, collectively referred to as the stop codon context (SCC). Here, we develop a high-content reporter system to precisely measure TR efficiency at different SCCs, assess the recovery of the full-length MeCP2 protein, and evaluate its subcellular localization. We have conducted a comprehensive investigation into the intricate relationship between SCC characteristics and TR induction, examining a total of 14 pathogenic MeCP2 nonsense mutations with the aim to advance the prospects of personalized therapy for individuals with RTT. Our results demonstrate that TR induction can successfully restore full-length MeCP2 protein, albeit to varying degrees, contingent upon the SCC and the specific position of the PTC within the MeCP2 mRNA. TR induction can lead to the re-establishment of nuclear localization of MeCP2, indicating the potential restoration of protein functionality. In summary, our findings underscore the significance of SCC-specific approaches in the development of tailored therapies for RTT. By unraveling the relationship between SCC and TR therapy, we pave the way for personalized, individualized treatment strategies that hold promise for improving the lives of individuals affected by this debilitating neurodevelopmental disorder. KEY MESSAGES: The efficiency of readthrough induction at MeCP2 premature termination codons strongly depends on the stop codon context. The position of the premature termination codon on the transcript influences the readthrough inducibility. A new high-content dual reporter assay facilitates the measurement and prediction of readthrough efficiency of specific nucleotide stop contexts. Readthrough induction results in the recovery of full-length MeCP2 and its re-localization to the nucleus. MeCP2 requires only one of its annotated nuclear localization signals.

Gut microbiota profile in CDKL5 deficiency disorder patients.

CDKL5 deficiency disorder (CDD) is a neurodevelopmental condition characterized by global developmental delay, early-onset seizures, intellectual disability, visual and motor impairments. Unlike Rett Syndrome (RTT), CDD lacks a clear regression period. Patients with CDD frequently encounter gastrointestinal (GI) disturbances and exhibit signs of subclinical immune dysregulation. However, the underlying causes of these conditions remain elusive. Emerging studies indicate a potential connection between neurological disorders and gut microbiota, an area completely unexplored in CDD. We conducted a pioneering study, analyzing fecal microbiota composition in individuals with CDD (n = 17) and their healthy relatives (n = 17). Notably, differences in intestinal bacterial diversity and composition were identified in CDD patients. In particular, at genus level, CDD microbial communities were characterized by an increase in the relative abundance of Clostridium_AQ, Eggerthella, Streptococcus, and Erysipelatoclostridium, and by a decrease in Eubacterium, Dorea, Odoribacter, Intestinomonas, and Gemmiger, pointing toward a dysbiotic profile. We further investigated microbiota changes based on the severity of GI issues, seizure frequency, sleep disorders, food intake type, impairment in neuro-behavioral features and ambulation capacity. Enrichment in Lachnoclostridium and Enterobacteriaceae was observed in the microbiota of patients with more severe GI symptoms, while Clostridiaceae, Peptostreptococcaceae, Coriobacteriaceae, Erysipelotrichaceae, Christensenellaceae, and Ruminococcaceae were enriched in patients experiencing daily epileptic seizures. Our findings suggest a potential connection between CDD, microbiota and symptom severity. This study marks the first exploration of the gut-microbiota-brain axis in subjects with CDD. It adds to the growing body of research emphasizing the role of the gut microbiota in neurodevelopmental disorders and opens doors to potential interventions that target intestinal microbes with the aim of improving the lives of patients with CDD.

Extending MeCP2 interactome: canonical nucleosomal histones interact with MeCP2.

MeCP2 is a general regulator of transcription involved in the repression/activation of genes depending on the local epigenetic context. It acts as a chromatin regulator and binds with exquisite specificity to gene promoters. The set of epigenetic marks recognized by MeCP2 has been already established (mainly, cytosine modifications in CpG and CpA), as well as many of the constituents of its interactome. We unveil a new set of interactions for MeCP2 with the four canonical nucleosomal histones. MeCP2 interacts with high affinity with H2A, H2B, H3 and H4. In addition, Rett syndrome associated mutations in MeCP2 and histone epigenetic marks modulate these interactions. Given the abundance and the structural/functional relevance of histones and their involvement in epigenetic regulation, this new set of interactions and its modulating elements provide a new addition to the 'alphabet' for this epigenetic reader.

Atypical brain responses to 40-Hz click trains in girls with Rett syndrome: Auditory steady-state response and sustained wave.

AIM: The current study aimed to infer neurophysiological mechanisms of auditory processing in children with Rett syndrome (RTT)-rare neurodevelopmental disorders caused by MECP2 mutations. We examined two brain responses elicited by 40-Hz click trains: auditory steady-state response (ASSR), which reflects fine temporal analysis of auditory input, and sustained wave (SW), which is associated with integral processing of the auditory signal. METHODS: We recorded electroencephalogram findings in 43 patients with RTT (aged 2.92-17.1 years) and 43 typically developing children of the same age during 40-Hz click train auditory stimulation, which lasted for 500 ms and was presented with interstimulus intervals of 500 to 800 ms. Mixed-model ancova with age as a covariate was used to compare amplitude of ASSR and SW between groups, taking into account the temporal dynamics and topography of the responses. RESULTS: Amplitude of SW was atypically small in children with RTT starting from early childhood, with the difference from typically developing children decreasing with age. ASSR showed a different pattern of developmental changes: the between-group difference was negligible in early childhood but increased with age as ASSR increased in the typically developing group, but not in those with RTT. Moreover, ASSR was associated with expressive speech development in patients, so that children who could use words had more pronounced ASSR. CONCLUSION: ASSR and SW show promise as noninvasive electrophysiological biomarkers of auditory processing that have clinical relevance and can shed light onto the link between genetic impairment and the RTT phenotype.

Exposure-Response Efficacy Modeling to Support Trofinetide Dosing in Individuals with Rett Syndrome.

INTRODUCTION: Trofinetide was recently approved for the treatment of Rett syndrome (RTT) on the basis of the efficacy and safety findings of the phase 3 LAVENDER study, which used a body weight-based dosing regimen. Exposure-response (E-R) efficacy modeling was used to characterize relationships between trofinetide exposure measures (maximum drug concentration and area under the concentration-time curve for the dosing interval of 0-12 h [AUC0-12]) and efficacy endpoints in RTT clinical studies to support the trofinetide dosing regimen. METHODS: Efficacy endpoints were modeled using trofinetide exposure measures predicted from the population pharmacokinetic model and Bayesian estimates. The analysis population for each E-R model comprised individuals receiving placebo or trofinetide who had available trofinetide exposure measures. Efficacy endpoints were scores from the Rett Syndrome Behaviour Questionnaire (RSBQ), the Clinical Global Impression-Improvement, the Communication and Symbolic Behavior Scales Developmental Profile™ Infant-Toddler Checklist (CSBS-DP-IT) Social Composite, and the Rett Syndrome Clinician Rating of Ability to Communicate Choices (RTT-COMC). RESULTS: Higher trofinetide exposure was associated with improvements in RSBQ, CSBS-DP-IT Social Composite, and RTT-COMC scores. Assuming target trofinetide AUC0-12 values of 800-1200 µg·h/mL, the reductions in RSBQ total scores at week 12 were approximately five- to seven-fold greater with trofinetide (range 3.55-4.94) versus placebo (0.76). Significant E-R relationships were also found for the CSBS-DP-IT Social Composite and RTT-COMC scores. CONCLUSION: E-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 REGISTRATION: NCT01703533, NCT02715115, NCT04181723.

Trofinetide is the first approved treatment for people living with Rett syndrome, a rare genetic condition affecting brain development. This approval was based on the findings of clinical studies in which trofinetide showed significant improvements in the symptoms of Rett syndrome. In this study researchers were looking to see if the level of trofinetide in the blood was related to the level of improvement in symptoms observed in clinical studies. Information on the effectiveness of trofinetide was obtained from the phase 3 LAVENDER study which used doses of trofinetide according to body weight. Trofinetide's effectiveness was assessed on the basis of clinical measurements of key Rett syndrome symptoms. All the information on trofinetide dose, blood levels, and how much symptoms changed (i.e., effectiveness of trofinetide) was then used to develop models to predict symptom responses in the observed population. Researchers found that as the blood levels of trofinetide increased the symptom improvement also increased. When the blood levels were at the recommended level that was achieved in the LAVENDER study, the model predicted that symptom improvement was up to seven times greater with trofinetide than having no treatment (i.e., placebo). This study shows a positive relationship between trofinetide blood levels and improvement in the symptoms of Rett syndrome. Trofinetide was effective within the recommended blood level range in the LAVENDER study using the approved weight-based dosing.

Managing Gastrointestinal Symptoms Resulting from Treatment with Trofinetide for Rett Syndrome: Caregiver and Nurse Perspectives.

Rett syndrome (RTT) is a rare genetic neurodevelopmental disorder mainly affecting female individuals. Trofinetide was recently approved as the first treatment for RTT, largely on the basis of results from the phase 3 LAVENDER trial, in which trofinetide showed improvements in core symptoms of RTT compared with placebo. However, gastrointestinal (GI) symptoms such as diarrhea and vomiting were commonly reported side effects, and taste was also a reported issue. The objective of this article is to describe the perspectives of five caregivers of girls in trofinetide clinical trials as well as those of three nurse trial coordinators, with a focus on management of GI symptoms of trofinetide treatment.Audio Abstract available for this article. Audio Abstract: Jane Lane provides an overview and discusses key findings of the article titled "Managing Gastrointestinal Symptoms Resulting from Treatment with Trofinetide for Rett Syndrome: Caregiver and Nurse Perspectives." (MP4 83274 KB).