Trofinetide

Most cases of Rett syndrome are associated with loss-of-function mutations in a gene encoding methyl CpG binding protein 2 (MECP2), a DNA binding protein with a role in epigenetic regulation of gene expression. These mutations are believed to lead to synaptic immaturation in the cortex, aberrant metabolism of brain cholesterol resulting in abnormal neuronal development, and abnormal neuronal signaling. Rett syndrome more commonly occurs in girls than boys.

The exact mechanism of action of trofinetide in Rett syndrome has not been fully elucidated. In mice studies, GPE improved motor and cardiorespiratory function, increased brain weight, and prolonged the lifespan in Mecp2-deficient mice. As a GPE analog, trofinetide similarly attenuated apoptosis and reduced infarct size in a dose-dependent manner in a rat model of hypoxic insult. Trofinetide exerts a multi-faceted action to reduce inflammation, excitotoxicity-induced tissue damage, and apoptosis, thereby protecting the neurons and their surrounding infrastructure.