# Innate Immunity Stimulation via CpG ODN in a Non-Human Primate Model of Sporadic Cerebral Amyloid Angiopathy

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $652,338

## Abstract

ABSTRACT
Several reports have outlined the potential benefit of therapeutically targeting mononuclear cells to reduce
Alzheimer's disease (AD) related pathology. Innate immune cells can exhibit dysfunctional/senescent profiles
characterized by impaired migration and phagocytosis as AD progresses. Therefore, modulating
macrophage/microglia profiles represents a potential therapeutic avenue to reduce AD pathology. We have
focused on reconciling the age related defects in immune cell function and tackling AD via Toll-like receptor 9
(TLR9). Our findings from multiple AD mouse models demonstrate that stimulation of innate immunity via TLR9
with CpG ODN can safely ameliorate all the pathological lesions that characterize AD without any toxicity. A
drawback of present immunotherapeutic approaches is a limited effectiveness against cerebral amyloid
angiopathy (CAA) and excessive neuroinflamation. Current evidence points to a key role for CAA in the
pathophysiology leading to development of amyloid-related imaging abnormalities (ARIA). Solving the problem
of CAA is becoming the priority for ensuring the success of immunotherapy. Our recent data from a biologically
advantageous non-human primate model of sporadic CAA, squirrel monkey (Saimiri Boliviensis), indicate that
treatment with CpG ODN results in cognitive improvements and a reduction of CAA in the absence of adverse
events. Here we propose using a TLR9 ligand, class B CpG ODN 1018 ISS, which has shown good safety
profiles in humans and is currently being tested in clinical trials for a variety of indications. The present study
will be the first to evaluate the 1018 ISS treatment effects and long term safety in aged squirrel monkeys with
established pathology, and will provide essential preclinical evidence for an IND application and subsequent
phase Ib testing of 1018 ISS in AD patients. 1018 ISS efficacy on CAA levels, as well as the low levels of
parenchymal amyloid deposits present in this model, will be correlated with behavioral assessments, biomarker
evaluation and MRI. Our novel MRI methodology, using bi-functional ultrasmall superparamagnetic iron oxide
(USPIO) nanoparticles coupled to polyethylene glycol (PEG) and A40, will allow 1018 ISS treatment effects
on amyloid burden to be followed longitudinally. Hence, our planned studies will also demonstrate the
suitability of USPIO-PEG-Aβ for future clinical trials. Furthermore, monitoring for ARIA will add further
complexity to evaluation of 1018 ISS efficacy and safety. The project described here is designed to
characterize gene expression and protein expression profiles involved in CpG ODN-mediated signaling and
phagocytic pathways. We plan to assess 1018 ISS immunostimulatory effects responsible for activating
macrophages/microglia towards beneficial phenotypes, which may contribute to clearance of CAA pathology.
We believe the proposed comprehensive assessments will help establish a panel of novel biomarkers and
determine appropriate out...

## Key facts

- **NIH application ID:** 9931327
- **Project number:** 5R01NS102845-04
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Henrieta Scholtzova
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $652,338
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9931327

## Citation

> US National Institutes of Health, RePORTER application 9931327, Innate Immunity Stimulation via CpG ODN in a Non-Human Primate Model of Sporadic Cerebral Amyloid Angiopathy (5R01NS102845-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9931327. Licensed CC0.

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