Novel brain-penetrant drugs for translation-targeting therapeutics of Alzheimer’s disease

Abstract
Alzheimer's disease (AD), the most common form of dementia in older adults, is a neurodegenerative
disorder characterized by progressive decline of memory and cognition. AD is multifaceted and heterogeneous,
which prevents clear mechanistic understanding of AD pathogenesis and therefore hinders development of
effective therapeutics. Meanwhile, post-mortem epidemiology indicated that AD onset was associated with
elevated activity of the histone methyltransferase G9a (EHMT2) in diseased brain,
implicating
G9a activity-
associated pathways in AD pathogenesis. Using our c
hromatin-activity-based chemoproteomic (ChaC)
approach that enables dissection of AD heterogeneity
, we (the Chen lab) have discovered a noncanonical,
translation regulatory function of G9a in AD pathogenesis. Further, we deduced the mechanism of action of a
brain-penetrant G9a-targetd drug,
MS1262,
w
here G9a inhibition by MS1262 reversed
AD patient proteomes,
particularly the AD-disturbed expression or phosphorylation of proteins related to cognition and learning, synaptic
transmission, synaptogenesis, and hyperactive behavior. Correspondingly, intermittent
MS1262 treatment
restored cognitive and affective functions in mid/late-stage 5xFAD mice to the healthy level (p <0.0027). Thus,
we will develop a new mechanism-based AD therapeutics. TransChromix, LLC, a startup company created by
the NC Kick-Start program, and Professor Xian Chen at the UNC School of Medicine, will conduct this project.
Our preliminary results show that MS1262 therapy of AD is clinically practical: Comparison of proteomic
analyses of MS1262-treated AD mice with human data from large cohorts of AD patients revealed that MS1262
reversed the patient proteomic landscapes that were highly correlated with AD pathology and cognitive decline.
This mouse-to-human conservation of G9a-translated AD proteomes suggests that the therapeutic effects of
MS1262 in mice could extend to AD patients. Thus, we will test the hypothesis that targeting G9a-mediated
translational mechanisms using brain-penetrant drugs is a specific and effective strategy to prevent and/or
reverse AD progression. In Phase I, we will test the hypothesis that targeting G9a-mediated translational
mechanisms using MS1262 is a specific and effective strategy to prevent and/or reverse AD progression.
Specifically, in the
MS1262
-treated AD mouse models including 5xFAD mice and other established AD mouse
models at different stages of AD progression we will (1) comprehensively determine the long-term efficacy and
the specificity of MS1262 on synaptic and cognitive function,
(2)
measure inhibitor toxicity and brain specificity
by dose range finding and pharmacokinetic studies, and (3) validate the clinical accuracy of G9a inhibitory
mechanism. In
Phase II
we will use the Phase I-optimized doses with low toxicity to test the treatment efficacy
for AD patients. Meanwhile, we will develop companion diagnostic assays to stratify patients for enhanced
therapy with high response rates. The end deliverable of phase II funding will be an FDA IND application.

Grant Number: 1R41AG085859-01
NIH Institute/Center: NIH
Principal Investigator: XIAN CHEN