Targeting the integrated stress response to treat Down syndrome

INDICATION: Cognitive dysfunction

Suppressing the integrated stress response (ISR) by activating EIF2B or inhibiting EIF2AK2 could treat Down syndrome. Levels of phosphorylation of EIF2AK2 and of its downstream target EIF2, both markers of ISR activation, were elevated in the hippocampus of mice with Down syndrome. Levels of phosphorylated EIF2 were also elevated in postmortem brain samples from patients compared with samples from euploid individuals. In a mouse model of Down syndrome that recapitulates the learning and memory deficits seen in patients, genetic or pharmacological inhibition of EIF2 phosphorylation, or an EIF2B activator that counters the effects of EIF2 phosphorylation, improved long-term memory...