# Long-Acting RNAi Therapy for Atherosclerosis and Insulin Resistance

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $711,340

## Abstract

ABSTRACT
With the ability to silence individual genes and to drug the ‘undruggable’, RNA interference (RNAi) therapy has
recently shown clinical success by delivering small interfering RNA (siRNA) to the liver for genetic diseases.
However, new delivery strategies will be needed to expand the targeting possibilities of siRNA therapy beyond
the liver for treatment of other diseases like atherosclerotic cardiovascular disease. We have therefore formed a
team with complementary expertise in siRNA delivery and atherosclerosis, and developed a targeted siRNA
delivery strategy to silence calcium/calmodulin-dependent kinase-IIγ (CaMKIIγ), a kinase that is activated in the
macrophages of human and mouse advanced atherosclerotic lesions and promotes progression of clinically
dangerous plaques. We showed that targeted siCamk2g treatment improved plaque stability by reducing necrotic
core area and increasing fibrous cap thickness. Nevertheless, due to the transient nature of siRNA-mediated
gene silencing, a critical challenge for siRNA therapy is the short duration of action. In this project, we propose
to i) explore a novel siRNA delivery strategy that can dramatically extend the duration of CaMKIIγ silencing in
atherosclerotic lesional macrophages; and ii) engineer the new siCamk2g platform for dual-cell targeting for
integrated treatment of obesity-induced type 2 diabetes and atherosclerosis. Our new preliminary work has
identified a distinct type of synthetic lipid-poly(ethylene glycol) (lipid-PEG) biomaterials that can markedly prolong
siRNA silencing and its blood circulation. We thus hypothesize that the new lipid-PEG-mediated long-acting
siCamk2g therapy could effectively target both atherosclerosis and insulin resistance with low dosing frequency.
In Aim 1, we will synthesize a series of such distinct lipid-PEG biomaterials; systematically explore the lipid-PEG
effects on the duration of action and pharmacokinetics of siRNA; and optimize the unique siRNA delivery platform
in a mouse model with established atherosclerosis. The lead candidate with longest duration of macrophage
CaMKIIγ silencing will be evaluated for efficacy in dampening atherosclerosis, with an emphasis on plaque
necrosis, fibrous cap thickness, and efferocytosis and other inflammation resolution endpoints. In Aim 2, we will
expand the long-acting siRNA therapy to dual-cell targeting for cardiometabolic disease, based upon the fact
that CaMKIIγ is a common upstream target in both hepatocytes in obesity-induced insulin resistance and lesional
macrophages in atherosclerosis. We will iteratively optimize the dual-targeting siCamk2g system in vitro and in
vivo, including in a new mouse model with combined insulin resistance and atherosclerosis, in a manner to
effectively improve type 2 diabetes and suppress atherosclerosis. We expect that successful completion of this
project will lead to fundamental understanding of how the new lipid-PEG chemistry controls siRNA delivery and
the devel...

## Key facts

- **NIH application ID:** 10277786
- **Project number:** 1R01HL159012-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Jinjun Shi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $711,340
- **Award type:** 1
- **Project period:** 2021-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10277786

## Citation

> US National Institutes of Health, RePORTER application 10277786, Long-Acting RNAi Therapy for Atherosclerosis and Insulin Resistance (1R01HL159012-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10277786. Licensed CC0.

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