Quantifiable protein biomarkers for Rett syndrome.
Rett syndrome is a progressive neurodevelopmental disorder that affects approximately one in 10,000 to 15,000 female births worldwide. It is caused by mutations on the X chromosome in the methyl-CpG-binding protein 2 (MECP2) gene, which modulates gene expression in neurons. Previous studies on Rett Syndrome have focused on either the defects in the transcriptome or behavioral phenotypes in animal models of the disorder. This conventional emphasis neglects the exploration of Rett syndrome proteomes, which identify/define the proteins being expressed that play a critical role in driving mechanisms responsible for behavioral phenotypes. Additionally, evaluating the outcomes of Rett syndrome gene therapies primarily relies on clinical indicators and lacks quantifiable biochemical biomarkers.
The inventors have identified protein biomarkers for Rett syndrome that can aid in assessing therapy effectiveness, target engagement, and disease severity. The inventors designed a strategy to quantify secreted proteomes from the cerebrospinal fluid (CSF) using tandem mass tagging (TMT) mass spectrometry and other quantitative proteome platforms. They observed protein expression changes in the CSF and brain in Mecp2 mutant animals compared to wildtype control animals. The inventors identified critical protein candidates that were validated in human CSF samples from patients with and without Rett syndrome. They also demonstrated in animal models that these proteins respond to Rett syndrome gene therapy. These findings demonstrate that protein biomarkers isolated from CSF and present in other biofluids can be good indicators to complement clinical assessments in patients with Rett syndrome.
Publication Zlatic, S. et al. (2022). iScience, 25(9) https://doi.org/10.1016/j.isci.2022.104966