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Pharmaceuticals (Basel, Switzerland) Feb 2024A total of nine TIDES (pepTIDES and oligonucleoTIDES) were approved by the FDA during 2023. The four approved oligonucleotides are indicated for various types of... (Review)
Review
A total of nine TIDES (pepTIDES and oligonucleoTIDES) were approved by the FDA during 2023. The four approved oligonucleotides are indicated for various types of disorders, including amyotrophic lateral sclerosis, geographic atrophy, primary hyperoxaluria type 1, and polyneuropathy of hereditary transthyretin-mediated amyloidosis. All oligonucleotides show chemically modified structures to enhance their stability and therapeutic effectiveness as antisense or aptamer oligomers. Some of them demonstrate various types of conjugation to driving ligands. The approved peptides comprise various structures, including linear, cyclic, and lipopeptides, and have diverse applications. Interestingly, the FDA has granted its first orphan drug designation for a peptide-based drug as a highly selective chemokine antagonist. Furthermore, Rett syndrome has found its first-ever core symptoms treatment, which is also peptide-based. Here, we analyze the TIDES approved in 2023 on the basis of their chemical structure, medical target, mode of action, administration route, and common adverse effects.
PubMed: 38399458
DOI: 10.3390/ph17020243 -
Brain Sciences Jan 2024Rett syndrome (RTT) is a neurological disorder that mostly affects females, with a frequency of 1 in 10,000 to 20,000 live birth cases. Symptoms include stereotyped hand... (Review)
Review
Rett syndrome (RTT) is a neurological disorder that mostly affects females, with a frequency of 1 in 10,000 to 20,000 live birth cases. Symptoms include stereotyped hand movements; impaired learning, language, and communication skills; sudden loss of speech; reduced lifespan; retarded growth; disturbance of sleep and breathing; seizures; autism; and gait apraxia. Pneumonia is the most common cause of death for patients with Rett syndrome, with a survival rate of 77.8% at 25 years of age. Survival into the fifth decade is typical in Rett syndrome, and the leading cause of death is cardiorespiratory compromise. Rett syndrome progression has multiple stages; however, most phenotypes are associated with the nervous system and brain. In total, 95% of Rett syndrome cases are due to mutations in the gene, an X-linked gene that encodes for the methyl CpG binding protein, a regulator of gene expression. In this review, we summarize the recent developments in the field of Rett syndrome and therapeutics targeting MECP2.
PubMed: 38391695
DOI: 10.3390/brainsci14020120 -
Advances in Therapy Apr 2024Rett syndrome (RTT) is a rare genetic neurodevelopmental disorder mainly affecting female individuals. Trofinetide was recently approved as the first treatment for RTT,...
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).
Topics: Female; Humans; Caregivers; Causality; Gastrointestinal Diseases; Glutamates; Rett Syndrome
PubMed: 38378975
DOI: 10.1007/s12325-024-02782-4 -
Exposure-Response Efficacy Modeling to Support Trofinetide Dosing in Individuals with Rett Syndrome.Advances in Therapy Apr 2024Trofinetide 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...
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 [AUC]) 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 AUC 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.
Topics: Humans; Infant; Bayes Theorem; Communication; Glutamates; Rett Syndrome
PubMed: 38363467
DOI: 10.1007/s12325-024-02796-y -
BioRxiv : the Preprint Server For... Feb 2024RNA editing offers the opportunity to introduce either stable or transient modifications to nucleic acid sequence without permanent off-target effects, but installation...
RNA editing offers the opportunity to introduce either stable or transient modifications to nucleic acid sequence without permanent off-target effects, but installation of arbitrary edits into the transcriptome is currently infeasible. Here, we describe Programmable RNA Editing & Cleavage for Insertion, Substitution, and Erasure (PRECISE), a versatile RNA editing method for writing RNA of arbitrary length and sequence into existing pre-mRNAs via 5' or 3' trans-splicing. In trans-splicing, an exogenous template is introduced to compete with the endogenous pre-mRNA, allowing for replacement of upstream or downstream exon sequence. Using Cas7-11 cleavage of pre-mRNAs to bias towards editing outcomes, we boost the efficiency of RNA trans-splicing by 10-100 fold, achieving editing rates between 5-50% and 85% on endogenous and reporter transcripts, respectively, while maintaining high-fidelity. We demonstrate PRECISE editing across 11 distinct endogenous transcripts of widely varying expression levels, showcasing more than 50 types of edits, including all 12 possible transversions and transitions, insertions ranging from 1 to 1,863 nucleotides, and deletions. We show high efficiency replacement of exon 4 of MECP2, addressing most mutations that drive the Rett Syndrome; editing of SHANK3 transcripts, a gene involved in Autism; and replacement of exon 1 of HTT, removing the hallmark repeat expansions of Huntington's disease. Whole transcriptome sequencing reveals the high precision of PRECISE editing and lack of off-target trans-splicing activity. Furthermore, we combine payload engineering and ribozymes for protein-free, high-efficiency trans-splicing, with demonstrated efficiency in editing HTT exon 1 via AAV delivery. We show that the high activity of PRECISE editing enables editing in non-dividing neurons and patient-derived Huntington's disease fibroblasts. PRECISE editing markedly broadens the scope of genetic editing, is straightforward to deliver over existing gene editing tools like prime editing, lacks permanent off-targets, and can enable any type of genetic edit large or small, including edits not otherwise possible with existing RNA base editors, widening the spectrum of addressable diseases.
PubMed: 38352602
DOI: 10.1101/2024.01.31.578223 -
BioRxiv : the Preprint Server For... Jan 2024The extraordinary diversity of neuron types in the mammalian brain is delineated at the highest resolution by subtle gene expression differences that may require...
The extraordinary diversity of neuron types in the mammalian brain is delineated at the highest resolution by subtle gene expression differences that may require specialized molecular mechanisms to be maintained. Neurons uniquely express the longest genes in the genome and utilize neuron-enriched non-CG DNA methylation (mCA) together with the Rett syndrome protein, MeCP2, to control gene expression, but the function of these unique gene structures and machinery in regulating finely resolved neuron type-specific gene programs has not been explored. Here, we employ epigenomic and spatial transcriptomic analyses to discover a major role for mCA and MeCP2 in maintaining neuron type-specific gene programs at the finest scale of cellular resolution. We uncover differential susceptibility to MeCP2 loss in neuronal populations depending on global mCA levels and dissect methylation patterns and intragenic enhancer repression that drive overlapping and distinct gene regulation between neuron types. Strikingly, we show that mCA and MeCP2 regulate genes that are repeatedly tuned to differentiate neuron types at the highest cellular resolution, including spatially resolved, vision-dependent gene programs in the visual cortex. These repeatedly tuned genes display genomic characteristics, including long length, numerous intragenic enhancers, and enrichment for mCA, that predispose them to regulation by MeCP2. Thus, long gene regulation by the MeCP2 pathway maintains differential gene expression between closely-related neurons to facilitate the exceptional cellular diversity in the complex mammalian brain.
PubMed: 38352532
DOI: 10.1101/2024.01.30.577861 -
Research Square Jan 2024Background 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...
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 100Hz 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.
PubMed: 38352397
DOI: 10.21203/rs.3.rs-3863341/v1 -
MedRxiv : the Preprint Server For... Jan 2024In 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,...
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 100Hz 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.
PubMed: 38343802
DOI: 10.1101/2024.01.25.24301723 -
Frontiers in Immunology 2023The association between gut microbiota and central nervous system (CNS) development has garnered significant research attention in recent years. Evidence suggests... (Review)
Review
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 stages of CNS development (prenatal and postnatal), emphasizing the integral role of gut microbes. Furthermore, the review explores the implications of gut microbiota in neurodevelopmental disorders, such as autism spectrum disorder, Rett syndrome, and Angelman syndrome, offering insights into early detection, prompt intervention, and innovative treatments.
Topics: Humans; Gastrointestinal Microbiome; Autism Spectrum Disorder; Central Nervous System Diseases; Central Nervous System
PubMed: 38343438
DOI: 10.3389/fimmu.2023.1288256 -
Orphanet Journal of Rare Diseases Feb 2024We aimed to develop a validated patient-reported Gastrointestinal Health Scale (GHS) specific to MECP2 Duplication Syndrome (MDS) to be used in clinical trials.
BACKGROUND/AIMS
We aimed to develop a validated patient-reported Gastrointestinal Health Scale (GHS) specific to MECP2 Duplication Syndrome (MDS) to be used in clinical trials.
METHODS
MDS parents completed a Gastrointestinal Health Questionnaire (GHQ) to investigate the most relevant and important items associated with gastrointestinal problems in MECP2-related disorders. Item reduction was executed according to EORTC guidelines. We performed reliability and validity studies for the finalized scale.
RESULTS
A total of 106 surveys were eligible for item reduction and validation processes. The initial 55 items were reduced to 38 items based on parent responses, expert opinion, and initial confirmatory factor analysis (CFA). The final MDS-specific GHS included 38 items and 7 factors that underwent further reliability and validity assessments. The power of the study was at least 0.982. The Cronbach's alphas of the instruments were General Health: 0.799, Eating-Chewing-Swallowing: 0.809, Reflux: 0.794, Motility: 0.762, Mood: 0.906, Medication: 0.595, Parenting: 0.942 and all items together: 0.928. The correlation coefficient between total and individual item scores ranged from 0.215 to 0.730. Because of the ordinal nature of the variables, the diagonal weighted least squares estimation (DWLS) method was used to execute the CFA and Structural Equation Modeling. The GHS had excellent model fit with the acceptable range of fit indices values.
CONCLUSIONS
We developed a parent-reported, reliable, and valid MDS-specific GHS. This scale can be utilized in clinical settings or as an outcome measure in translational and clinical research.
Topics: Humans; Reproducibility of Results; Psychometrics; Parents; Mental Retardation, X-Linked; Surveys and Questionnaires
PubMed: 38331915
DOI: 10.1186/s13023-024-03022-2