Preclinical characterization of splice-modifying antisense oligonucleotides targeting neurogenesis in human AD neural cells

PROJECT SUMMARY There is an enormous need for therapeutics to prevent and treat Alzheimer’s disease (AD). Adult Hippocampal Neurogenesis (AHN) is critical for normal learning and memory, but it declines in patients with AD. Work in animal models has underscored the role of AHN in improving cognition in the face of AD pathology. Augmenting AHN represents a promising potential avenue to promote cognitive function in the setting of mild cognitive impairment or Alzheimer’s disease, as well as in other neurological conditions. In this Phase I effort, we will evaluate lead candidate exon-skipping antisense oligonucleotides (ASOs) in human neural cell culture. Our ASOs have already demonstrated successful target modulation in two human cell types and in vivo efficacy studies are ongoing. These proposed studies represent an important advancement in our development efforts as they will generate data on our ability to modulate our target in cells that are physiologically highly similar to our ultimate target cell of interest, and may lead to biomarker identification. We will use these ASOs in validated patient cell lines in two “AD environments” to study their ability to achieve successful exon skipping, alter protein expression, and modulate signaling and function. Exon-skipping ASOs have emerged as effective and safe agents for regulating alternative splicing in the CNS, and significant advancements are ongoing with respect to non-invasive and minimally invasive routes of administration that would permit broad clinical implementation. Determining in vitro efficacy of our candidate ASOs is a critical step towards developing a highly targeted, safe and effective therapeutic for promoting AHN and improving cognition in AD. If successful, these studies would provide significant biological validation of the therapeutic potential of our candidate ASOs for the treatment or prevention of AD and other neurological conditions, and will enable us to build additional support as we works towards an Investigational New Drug Application with FDA.