Molecular Signatures of Response to Mecasermin in Children With Rett Syndrome

Frontiers in Neuroscience

卷:16

Chloe Delepine¹  Mriganka Sur¹  Walter E. Kaufmann³  Lindsay Swanson⁴  Mustafa Sahin⁴  Daniela Tropea⁵  Stephen Shovlin⁶  Snow Bach⁶ 

[1] Department of Brain and Cognitive Sciences, Simons Center for the Social Brain, Picower Institute for Learning and Memory, MIT, Cambridge, MA, United States;

[2] Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, United States;

[3] Department of Neurology, Boston Children’s Hospital, Boston, MA, United States;

[4] Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital and Harvard Medical School, Boston, MA, United States;

[5] FutureNeuro, The SFI Research Centre for Chronic and Rare Neurological Diseases, Dublin, Ireland;

[6] Neuropsychiatric Genetics, Trinity Center for Health Sciences, Trinity Translational Medicine Institute, St James Hospital, Dublin, Ireland;

[7] Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland;

关键词: Rett syndrome;    mecasermin;    insulin-like growth factor 1 (IGF1);    methyl-CpG binding protein 2 (MECP2);    biomarker;   

DOI  :  10.3389/fnins.2022.868008

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown