Molecular Signatures of Response to Mecasermin in Children With Rett Syndrome

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Rett syndrome (RTT) is a severe neurodevelopmental disorder with limited treatment options.
• Variability in RTT genotype and phenotype complicates targeted therapy development.
• Insulin-like Growth Factor 1 (IGF-1) shows promise in preclinical models but has inconsistent clinical trial results.

Purpose of the Study:

• To identify molecular biomarkers for treatment response in RTT patients receiving mecasermin (IGF-1).
• To stratify patients based on gene expression profiles and breathing phenotype.
• To explore surrogate endpoints for future clinical trials.

Main Methods:

• RNA sequencing was used to analyze whole blood gene expression in RTT patients from a Phase I mecasermin trial.
• Participants were subclassified based on breathing phenotype improvement (apnea index).
• Differential gene expression was compared between responders and a reference group.

Main Results:

• No significant gene expression changes were observed when all patients were analyzed together.
• Patients with moderate-severe apnea and breathing improvement (Responders) showed distinct transcript profiles compared to the Mecasermin Study Reference (MSR) group.
• The MSR group exhibited significant changes in genes related to inflammatory and immune processes, while responders showed fewer changes.

Conclusions:

• Gene expression profiles are associated with severe breathing phenotype and its improvement following mecasermin treatment in RTT.
• Inflammatory/immune pathways and IGF-1 signaling appear to influence treatment response.
• Transcript profiles show potential as biomarkers for predicting response to IGF-1 therapies in RTT.