Functional Network Mapping Reveals State-Dependent Response to IGF1 Treatment in Rett Syndrome

Keogh, Conor; Pini, Giorgio; Gemo, Ilaria; Kaufmann, Walter E.; Tropea, Daniela

doi:10.3390/brainsci10080515

Cited by 5 publications

(6 citation statements)

References 56 publications

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“…Nonetheless, IGF-1, BDNF, and apnoea-related genes were also differential at later time points suggesting continuous action of IGF-1 on target pathways. This molecular dynamics resembles the effects of mecasermin on brain activity in participants with RTT, as previously reported by us ( Keogh et al, 2020 ). The reason for the MSR group’s greater changes in gene expression, in response to mecasermin, is unknown and deserves further examination since these molecular changes may disclose key events associated with response to IGF-1 and related compounds.…”

Section: Discussionsupporting

confidence: 87%

Molecular Signatures of Response to Mecasermin in Children With Rett Syndrome

Shovlin¹,

Delépine²,

Swanson

et al. 2022

Front. Neurosci.

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Rett syndrome (RTT) is a devastating neurodevelopmental disorder without effective treatments. Attempts at developing targetted therapies have been relatively unsuccessful, at least in part, because the genotypical and phenotypical variability of the disorder. Therefore, identification of biomarkers of response and patients’ stratification are high priorities. Administration of Insulin-like Growth Factor 1 (IGF-1) and related compounds leads to significant reversal of RTT-like symptoms in preclinical mouse models. However, improvements in corresponding clinical trials have not been consistent. A 20-weeks phase I open label trial of mecasermin (recombinant human IGF-1) in children with RTT demonstrated significant improvements in breathing phenotypes. However, a subsequent randomised controlled phase II trial did not show significant improvements in primary outcomes although two secondary clinical endpoints showed positive changes. To identify molecular biomarkers of response and surrogate endpoints, we used RNA sequencing to measure differential gene expression in whole blood samples of participants in the abovementioned phase I mecasermin trial. When all participants (n = 9) were analysed, gene expression was unchanged during the study (baseline vs. end of treatment, T0–T3). However, when participants were subclassified in terms of breathing phenotype improvement, specifically by their plethysmography-based apnoea index, individuals with moderate-severe apnoea and breathing improvement (Responder group) displayed significantly different transcript profiles compared to the other participants in the study (Mecasermin Study Reference group, MSR). Many of the differentially expressed genes are involved in the regulation of cell cycle processes and immune responses, as well as in IGF-1 signalling and breathing regulation. While the Responder group showed limited gene expression changes in response to mecasermin, the MSR group displayed marked differences in the expression of genes associated with inflammatory processes (e.g., neutrophil activation, complement activation) throughout the trial. Our analyses revealed gene expression profiles associated with severe breathing phenotype and its improvement after mecasermin administration in RTT, and suggest that inflammatory/immune pathways and IGF-1 signalling contribute to treatment response. Overall, these data support the notion that transcript profiles have potential as biomarkers of response to IGF-1 and related compounds.

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Section: Discussionsupporting

confidence: 87%

Molecular Signatures of Response to Mecasermin in Children With Rett Syndrome

Shovlin¹,

Delépine²,

Swanson

et al. 2022

Front. Neurosci.

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“…It implied that insulin or insulin-like factor pathways might play an important role in the pathogenesis of RTT or RTT-like syndrome. It has been reported that IGF1 could ameliorate RTT-relevant phenotypes in animal models and improve some clinical manifestations in clinical trials (Pini et al, 2012 ; Keogh et al, 2020 ). Since possessing the ability to bind and regulate the expression of IGF1R, it is very likely that PRKD1 is a novel contributor to the clinical phenotypes of FOXG1-related disorder.…”

Section: Discussionmentioning

confidence: 99%

Identification of a de novo mutation of the FOXG1 gene and comprehensive analysis for molecular factors in Chinese FOXG1-related encephalopathies

Zhang²,

Xia

et al. 2022

Front. Mol. Neurosci.

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BackgroundFOXG1-related encephalopathy, also known as FOXG1 syndrome or FOXG1-related disorder, affects most aspects of development and causes microcephaly and brain malformations. This syndrome was previously considered to be the congenital variant of Rett syndrome. The abnormal function or expression of FOXG1, caused by intragenic mutations, microdeletions or microduplications, was considered to be crucial pathological factor for this disorder. Currently, most of the FOXG1-related encephalopathies have been identified in Europeans and North Americans, and relatively few Chinese cases were reported.MethodsArray-Comparative Genomic Hybridization (Array-CGH) and whole-exome sequencing (WES) were carried out for the proband and her parent to detect pathogenic variants.ResultsA de novo nonsense mutation (c.385G>T, p.Glu129Ter) of FOXG1 was identified in a female child in a cohort of 73 Chinese children with neurodevelopmental disorders/intellectual disorders (NDDs/IDs). In order to have a comprehensive view of FOXG1-related encephalopathy in China, relevant published reports were browsed and twelve cases with mutations in FOXG1 or copy number variants (CNVs) involving FOXG1 gene were involved in the analysis eventually. Feeding difficulties, seizures, delayed speech, corpus callosum hypoplasia and underdevelopment of frontal and temporal lobes occurred in almost all cases. Out of the 12 cases, eight patients (66.67%) had single-nucleotide mutations of FOXG1 gene and four patients (33.33%) had CNVs involving FOXG1 (3 microdeletions and 1 microduplication). The expression of FOXG1 could also be potentially disturbed by deletions of several brain-active regulatory elements located in intergenic FOXG1-PRKD1 region. Further analysis indicated that PRKD1 might be a cooperating factor to regulate the expression of FOXG1, MECP2 and CDKL5 to contribute the RTT/RTT-like disorders.DiscussionThis re-analysis would broaden the existed knowledge about the molecular etiology and be helpful for diagnosis, treatment, and gene therapy of FOXG1-related disorders in the future.

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“…[84][85][86] Glatiramer acetate has also demonstrated reduction in EEG abnormalities (eg, decreased epileptiform discharges). 87 Finally, Keogh et al 88 investigated the impact of IGF1 on network formation in responders in comparison to nonresponders based on clinical assessments. There was a significant difference in network measures that was predicted with 100% accuracy using a machine learning model applied to pretreatment data and highlighted the promise that quantitative EEG analysis has a role as a biomarker in clinical trials.…”

Section: Rett Syndromementioning

confidence: 99%

“…There was a significant difference in network measures that was predicted with 100% accuracy using a machine learning model applied to pretreatment data and highlighted the promise that quantitative EEG analysis has a role as a biomarker in clinical trials. 88 Rett syndrome may also be a candidate for gene replacement therapy as even postnatal rescue of the genotype demonstrates rescue of the behavioral, motor, and EEG phenotype. 89…”

Section: Rett Syndromementioning

confidence: 99%

Electroencephalographic (EEG) Biomarkers in Genetic Neurodevelopmental Disorders

et al. 2023

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Collectively, neurodevelopmental disorders are highly prevalent, but more than a third of neurodevelopmental disorders have an identifiable genetic etiology, each of which is individually rare. The genes associated with neurodevelopmental disorders are often involved in early brain development, neuronal signaling, or synaptic plasticity. Novel treatments for many genetic neurodevelopmental disorders are being developed, but disease-relevant clinical outcome assessments and biomarkers are limited. Electroencephalography (EEG) is a promising noninvasive potential biomarker of brain function. It has been used extensively in epileptic disorders, but its application in neurodevelopmental disorders needs further investigation. In this review, we explore the use of EEG in 3 of the most prevalent genetic neurodevelopmental disorders—Angelman syndrome, Rett syndrome, and fragile X syndrome. Quantitative analyses of EEGs, such as power spectral analysis or measures of connectivity, can quantify EEG signatures seen on qualitative review and potentially correlate with phenotypes. In both Angelman syndrome and Rett syndrome, increased delta power on spectral analysis has correlated with clinical markers of disease severity including developmental disability and seizure burden, whereas spectral power analysis on EEG in fragile X syndrome tends to demonstrate abnormalities in gamma power. Further studies are needed to establish reliable relationships between quantitative EEG biomarkers and clinical phenotypes in rare genetic neurodevelopmental disorders.

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Functional Network Mapping Reveals State-Dependent Response to IGF1 Treatment in Rett Syndrome

Cited by 5 publications

References 56 publications

Molecular Signatures of Response to Mecasermin in Children With Rett Syndrome

Molecular Signatures of Response to Mecasermin in Children With Rett Syndrome

Identification of a de novo mutation of the FOXG1 gene and comprehensive analysis for molecular factors in Chinese FOXG1-related encephalopathies

Electroencephalographic (EEG) Biomarkers in Genetic Neurodevelopmental Disorders

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