# Elucidating the contribution of lung epithelial gain of function toxicity to AATD disease pathogenesis

> **NIH NIH P01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2024 · $584,245

## Abstract

Summary/Abstract: Project 2
AATD is among the most common monogenic lung diseases, affecting an estimated 100,000 individuals in the
US and causing significant morbidity and mortality. Lung disease in AATD is classically attributed to low levels
of AAT in the lung resulting in protease-antiprotease imbalance and typically manifests in the form of
emphysema, identified in 100% of NHLBI longitudinal cohort participants with lung tissue available for analysis
at the time of death or lung transplant. Studies have found that severely deficient “ZZ” individuals, who
inherited two copies of the mutant “Z” allele (as opposed the normal “M” allele), collectively experience lung
function decline at an accelerated rate relative to those with “usual” COPD but have likewise demonstrated
highly variable rates of lung function decline over time among this population, suggesting that factors in
addition to antiprotease levels might contribute to injury. AAT augmentation therapy that normalizes both
circulating and epithelial lining fluid AAT levels provides a theoretical solution to “loss-of-function” injury that
results from protease-antiprotease imbalance and is the standard of care for “ZZ” individuals with impaired lung
function. Despite its ability to restore circulating AAT levels to exceed the therapeutic protective threshold,
however, efficacy was surprisingly challenging to establish, with multiple studies unable to conclusively
demonstrate significant reduction in FEV1 decline, consistent with the possibility that mechanisms in addition
to loss-of-function injury could be contributing. Based on this rationale and supported by provocative
preliminary data demonstrating toxicity in human primary AT2s expressing ZAAT, this proposal will test the
hypothesis that lung epithelial ZAAT protein production induces gain-of-function toxicity that contributes to lung
disease pathogenesis in ZZ AATD. To do so, it will leverage reagents including novel mice engineered to allow
conditional expression of ZAAT from specific lineages as well as patient-derived iPSC-type 2 cells to test the
effects of ZAAT expression alone or in combination with environmental injury on AT2 function and
predisposition to emphysema. It will then examine the effects of modulating specific cellular pathways on the
consequences of ZAAT expression in AT2s. Collectively, these experiments have the potential to suggest
novel treatment strategies for AATD-associated emphysema.

## Key facts

- **NIH application ID:** 10768966
- **Project number:** 1P01HL170952-01
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** ANDREW A WILSON
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $584,245
- **Award type:** 1
- **Project period:** 2024-03-01 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10768966

## Citation

> US National Institutes of Health, RePORTER application 10768966, Elucidating the contribution of lung epithelial gain of function toxicity to AATD disease pathogenesis (1P01HL170952-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10768966. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*