Development of a RUNX1 modulator to slow cognitive decline in Alzheimer's disease

PROJECT SUMMARY An estimated 6.9 million people over the age of 65 in the US are living with Alzheimer’s disease (AD), experiencing debilitating memory loss and physical impairments. Novel therapeutic treatments beyond those targeting amyloid beta (Aβ) are essential to address the immense universal burden of AD. Age-associated microglial dysfunction and accumulation of senescent microglia are increasingly recognized as mediators of mild cognitive impairment and AD. Thus, modulating microglial function in AD represents a distinct therapeutic approach that may lead to safe and effective treatments to slow the progression and potentially prevent the onset of AD. We hypothesize that the transcription factor RUNX1 is a driver of microglial dysfunction that results in cognitive decline with age. We have developed RUNX1-targeting antisense oligonucleotides capable of lowering RUNX1 expression both in murine primary microglia and in vivo in mice. The goal of this Phase I proposal is to identify a lead RUNX1 ASO development candidate and demonstrate therapeutic potential of RUNX1 ASOs for the treatment of AD. Specifically, we will: 1) conduct lead ASO therapeutic optimization to improve the safety and potency profile, and 2) demonstrate efficacy in a mouse model of AD using molecular biomarkers and behavioral endpoints. The proposed work will provide proof-of-concept for targeting RUNX1 as a novel approach to slow the cognitive decline in AD.