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Principal Investigator: KATHLEEN E. RODGERS
Organization: UNIVERSITY OF ARIZONA
Fiscal Year: 2022
Award: $383,750
Funding agency: National Institute on Aging
Activation of brain inflammatory pathways contributes to amyloid accumulation, neuronal dysfunction, cognitive
impairment, and memory loss which are the main pathological features of Alzheimer's disease (AD). There are
few treatments for AD and those available have limited utility. As a result, there is a desperate need for therapies
involving novel targets for the treatment of AD. Part of the difficulty in the development of therapeutics for AD is
the heterogeneity of the population and etiology as well as the insensitivity of the endpoints, particularly in early-
stage clinical trials. For these early trials, outcome measures focused on target engagement or biological
pathway analysis might improve trial outcomes and better support the drug development process.
Based upon these compelling data, we have chosen RASRx1902 as our clinical candidate for AD. Based on
conversations with key AD opinion leaders, it is crucial that we have biomarkers of target engagement and
efficacy for use in clinical trials. This proposal requests support to identify blood biomarkers of RASRx1902 target
engagement to facilitate dose optimization and patient enrollment during the clinical study of RASRx1902 in AD
patients. Using the known mechanisms by which Mas agonists reduced neurodegeneration, we hypothesize that
Mas agonism will reduce markers of neuronal death, astrogliosis, inflammation and oxidative stress.
Amendment Aim 1. Classically, the biomarkers used to monitor the degree of neurological injury include those
that reflect direct neuronal damage (phosphorylated Tau, p-Tau) and astrogliosis as well as blood-based
biomarkers such as neurofilament light, S100 calcium binding protein B, and ubiquitin carboxyl-terminal
hydrolase isoenzyme L1. Therefore, in Aim 1, we assess the effects of RASRx1902 treatment on these classic
neurodegenerative biomarkers.
Amendment Aim 2. To take an unbiased approach to biomarker discovery, we will use SomaScan (an aptamer-
based system that measures 7,000 proteins in the plasma) and Metabolon’s Global Metabolomics™ (an LC-MS
global metabolomics platform) to identify pathways both altered in AD and by RASRx1902. We will analyze and
correlate the data acquired by SomaScan with cognition and neurological changes. Comprehensive
metabolomic and lipidomic analyses will be conducted at Metabolon using their Global Metabolomics (>1000
metabolites involved in amino acid, carbohydrate, energy, lipid and nucleotide metabolism).
Amendment Aim 3. In Aim 3, we will seek to correlate the peripheral markers — the neurodegenerative
biomarkers (Aim 1) and the unbiased biomarkers (Aim 2) — with cognitive function and brain pathology, microglial
activation, astrogliosis and amyloid burden. Exploratory analyses will include pathway enrichment analyses,
multivariable visualization. Statistical hypothesis will be generated based on analyte differences between the
RASRx1902 and vehicle treated 5xFAD and WT at multiple time points. From these analyses, biomarker
discovery will be conducted.
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