# Targeting Angiopoietin-2 in ARDS

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $447,835

## Abstract

The acute respiratory distress syndrome (ARDS) is a common and devastating complication of sepsis that is
characterized by flooded lungs, need for mechanical ventilation, and severely low blood oxygen levels. ARDS
inflicts a very high mortality yet pharmacoprevention or pharmacotherapy options are lacking. In addition, the
risk for ARDS is incompletely explained by clinical factors suggesting that individual risk factors may be
important. We previously identified and replicated a genetic variant in the angiopoietin-2 gene (ANGPT2) that
strongly associated with ARDS risk. We demonstrated that carriers of the ARDS-associated genetic variant
exhibited a higher proportion of full-length angiopoietin-2 (ANG2) isoform in plasma, suggesting to us that
some patients are genetically predisposed to develop ARDS via the ANGPT2 gene, and that this risk may be
mediated by changes in plasma expression of ANG2. We used genetic regulation of plasma ANG2 during
sepsis, in a Mendelian Randomization analysis, to demonstrate that plasma ANG2 has a causal effect on the
risk of ARDS. Thus our long term objectives are to identify subjects who will benefit from anti-ANG2 therapy
and to develop compounds that effectively antagonize ANG2 as an early ARDS treatment. For this application,
we will identify and validate thresholds of plasma ANG2 that objectively increase or decrease ARDS risk using
classification and regression tree (CART) methodology on 2 large cohorts of critically ill patients with sepsis
who are carefully phenotyped for ARDS. The output will be plasma thresholds that might help to include or
exclude subjects for a future precision trial of anti-ANG2 therapy targeted to those likely to benefit. We will
enact Mendelian Randomization analysis to test whether the true effect of day 0 and day 2 plasma ANG2
towards ARDS mortality is causal, because this could inform the utility of anti-ANG2 therapy for prevention
alone versus for prevention and treatment. Finally, we will use a novel platform known as ex vivo lung
perfusion (EVLP), whereby lungs declined for transplantation are ventilated and perfused in a highly controlled
environment, to test whether 2 drugs that mimic ANG1 to activate the TIE2 receptor achieve an improved
phosphoTIE2/TIE2 ratio and improved oxygenation and lung compliance after a one-time dose. The
multidisciplinary team of investigators and consultants to enact these aims include 2 EVLP experts, 2
epidemiologists with expertise in lung injury prediction and molecular subphenotyping, a nanomedicine
pharmacologist with expertise in rational drug design, and the PI, a translational scientist who first identified a
link between ANGPT2 variation, plasma protein expression, and ARDS risk. Completion of these aims will
provide key data to inform a future precision anti-ANG2 trial for ARDS, including who should be enrolled,
whether the trial should focus on ARDS prevention or treatment, and which drug(s) to test.

## Key facts

- **NIH application ID:** 10125187
- **Project number:** 5R01HL137006-05
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Nuala Jennings Meyer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $447,835
- **Award type:** 5
- **Project period:** 2017-03-16 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10125187

## Citation

> US National Institutes of Health, RePORTER application 10125187, Targeting Angiopoietin-2 in ARDS (5R01HL137006-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10125187. Licensed CC0.

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