# Functional Characterization of ABCA3 Genomic Variants

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $474,436

## Abstract

PROJECT SUMMARY
Neonatal respiratory distress syndrome (RDS) is traditionally attributed to developmentally regulated disruption
of pulmonary surfactant production. However, studies of term infants with lethal RDS have led to the discovery
of genetically regulated disruption of functional surfactant production. Rare or private, biallelic, pathogenic
variants in the ATP binding cassette transporter A3 gene (ABCA3) are the most common monogenic causes of
neonatal RDS in term infants and childhood interstitial lung disease (chILD). ABCA3 transports phospholipids
across the lamellar body limiting membrane in alveolar type II cells and is required for packaging of functional
surfactant. Pathogenic ABCA3 variants encode (1) disruption of intracellular trafficking, (2) impairment of ATP-
ase mediated, phospholipid transport into the lamellar body, and may also (3) activate intracellular stress and
degradation pathways that disrupt lung function. Current treatments (surfactant replacement, steroids,
azithromycin, and hydroxychloroquine) are non-specific and ineffective. Lung transplantation, with a 5 year
survival of ~50%, remains the only treatment for progressive respiratory failure in affected infants and children.
 Development of variant-specific therapies for patients with pathogenic variants in the cystic fibrosis
transmembrane conductance regulator gene (CFTR), a member of the ABC transporter superfamily (ABCC7),
can provide a model for development of variant-specific therapies for ABCA3, although correctors will likely be
gene- and variant-specific.
 The premise of this proposal is to develop a scalable, functional genomics platform for mechanistic
characterization of ABCA3 variants and for compound screening and identification of small molecule correctors
in a human, pulmonary epithelial, physiologically-relevant cell line. Specifically, we will use clonally derived A549
cell lines that stably express individual ABCA3 pathogenic variants for (1) fluorescence-based, functional assays,
(2) characterization of variant-specific, pathogenic cellular degradation pathway activation, and (3) screening of
FDA-approved compounds for rescue of variant-encoded ABCA3 intracellular mistrafficking and pathogenic
degradation pathway activation to test hypothesis that variant-encoded ABCA3 mistrafficking and
pathogenic activation of cellular stress and degradation pathways can be mechanistically characterized
and can be corrected with FDA-approved small molecules.
 These studies will provide proof of principle for a scalable, functional, physiologically-relevant genomics
platform to discover variant-specific therapies for infants and children with ABCA3 deficiency. Additionally, this
genetically versatile system can be adapted and extended to discover targeted therapies for patients with other
monogenic diseases that disrupt surfactant function or pulmonary epithelial cell metabolism.

## Key facts

- **NIH application ID:** 10105361
- **Project number:** 5R01HL149853-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jennifer Wambach
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $474,436
- **Award type:** 5
- **Project period:** 2020-02-15 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10105361

## Citation

> US National Institutes of Health, RePORTER application 10105361, Functional Characterization of ABCA3 Genomic Variants (5R01HL149853-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10105361. Licensed CC0.

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