# TRAF6 Nanoimmunotherapy to resolve plaque inflammation

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $815,005

## Abstract

SUMMARY
 Atherosclerotic plaque regression as a result of lipid-lowering treatment has been limited at best, with
coronary artery disease (CAD) related event rates remaining unacceptably high.
 In this application, we propose that targeted immunomodulation of macrophages will resolve plaque
inflammation and beneficially impacts myocardial infarction-induced monocytosis’ detrimental effects. To that
aim, we have developed novel ‘nanobiologic’, a bioengineered version of our body’s own high density
lipoprotein (HDL) nanoparticle that specifically targets (plaque) myeloid cells6,7. The HDL nanobiologic contains
a small molecule inhibitor (TRAF6i), directed against the binding domain of CD40 on TRAF6, to specifically
block CD40-TRAF6 interactions.
 Based on these preliminary data in Apoe–/– mice and nonhuman primates, we propose — in two
independent Specific Aims — TRAF6i-HDL’s application to (i) prevent atherosclerotic plaque aggravation due
to myocardial infarction in Apoe–/– mice and (ii) induce plaque regression in a nonhuman primate
atherosclerosis model.
In Aim 1, we will execute a longitudinal and imaging-guided therapeutic study, involving a one-week high-dose
and a four-week low-dose TRAF6i-HDL regimen in atherosclerotic Apoe–/– mice. In the same mouse model, we
will apply TRAF6i-HDL nano-immunotherapy to prevent plaque aggravation after myocardial infarction, by
preventing the detrimental accumulation of inflammatory monocytes in the vessel wall. In Aim 2, based on our
extensive mouse efficacy data and imaging data in nonhuman primates, we will employ TRAF6i-HDL nano-
immunotherapy to regress established plaques in nonhuman primates. Positron emission tomography with
magnetic resonance imaging (PET/MRI) methods will serve as readouts for TRAF6i-HDL’s in vivo behavior
and therapeutic efficacy.
 In light of the promising CANTOS trial data, demonstrating a reduction in recurrent rates in
cardiovascular patients that were treated with a targeted anti-inflammatory therapy, successful completion of
this application’s aims will pave the way for potential clinical translation.

## Key facts

- **NIH application ID:** 10210324
- **Project number:** 5R01HL144072-04
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Zahi A. Fayad
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $815,005
- **Award type:** 5
- **Project period:** 2018-08-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10210324

## Citation

> US National Institutes of Health, RePORTER application 10210324, TRAF6 Nanoimmunotherapy to resolve plaque inflammation (5R01HL144072-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10210324. Licensed CC0.

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