AUTHOR=Shovlin Stephen , Delepine Chloe , Swanson Lindsay , Bach Snow , Sahin Mustafa , Sur Mriganka , Kaufmann Walter E. , Tropea Daniela TITLE=Molecular Signatures of Response to Mecasermin in Children With Rett Syndrome JOURNAL=Frontiers in Neuroscience VOLUME=16 YEAR=2022 URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2022.868008 DOI=10.3389/fnins.2022.868008 ISSN=1662-453X ABSTRACT=
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 (