Brain Mecp2 Genetic Dosage and Gene Therapy Shape Multi-omics Signatures and Biomarkers in Rett Syndrome [2]

Both the Mecp2-responsive proteome or the congruent 119 transcript-proteins pairs were enriched in synaptic and metabolic pathways including mitochondria carbon and NAD+ metabolism. We used this genetically validated and therapy-responsive library of proteins to inform the selection of putative biomarkers in cerebrospinal fluid of Rett patients. We analyzed cerebrospinal fluid composition of neurotypical and Rett subjects using an ultrasensitive nucleic acid based multiplexed ELISA.

We identified 28 proteins altered in Rett patients, 9 of which overlapped with proteins sensitive to gene therapy and dosage. Multivariate regression linked several candidate biomarkers to Mecp2/MECP2 protein abundance and phenotypic improvements in mice. Our paradigm provides a rigorous molecular systems-level framework integrating genetics, preclinical MECP2 gene therapy, and rodent clinical metrics to define robust, cross-species biomarkers and mechanisms in Rett syndrome and other neurodevelopmental disorders.