# Pathogenesis-Based Diagnostics and Pharmacotherapeutics for PAP

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $397,500

## Abstract

ABSTRACT
Despite our vastly improved understanding of pulmonary alveolar proteinosis (PAP) – a syndrome of surfactant
accumulation and respiratory failure that occurs in multiple diseases; clinically, PAP is usually evaluated using methods
(e.g., lung biopsy) unable to identify the PAP-causing disease and no drug is FDA-approved to treat it. One PAP-causing
disease, autoimmune PAP (aPAP), is mediated by GM-CSF autoantibodies (GMAbs) and accounts for more than 90% of
all cases. Importantly, while multiple clinical trials and an increasing of reports in the medical literature document the
efficacy, safety and tolerability of inhaled GM-CSF therapy of aPAP, the use of outcome measures not yet validated in
this patient population is a major barrier to regulatory approval. Low prevalence, underuse of effective diagnostics
(leading to misdiagnosis and under-detection), and little knowledge of the kinetics by which GM-CSF regulates surfactant
clearance by AMs comprise additional hurdles to pharmacotherapeutic development. In the prior funding periods, we
developed a panel of pathogenesis-based blood tests including one – the Serum GMAb Test – that is 100% sensitive and
specific for aPAP and is now the ‘gold standard’ for aPAP diagnosis. We also developed a dried blood spot card (DBSC)
version of this test – the DBSC GMAb Test – and validated it in the laboratory against the Serum GMAb Test. Another
test – the EC50-GM-CSF Signaling Test – identifies the amount of exogenous GM-CSF that must be added to heparinized
blood (aPAP or control) to stimulate GM-CSF signaling. Finally, we found that serum cholestenoic acid and automated
computer analysis of chest CT scans (using CALIPER software) can be used to measure disease severity and treatment
responses in aPAP patients. We plan to test the following central hypothesis: mediators driving the pathogenesis of
aPAP provide the basis for outstanding tests for diagnosis of aPAP, therapeutic GM-CSF dose-prediction, disease severity
monitoring, and treatment response measurement. This hypothesis is strongly supported by our Preliminary Data.
Further, the feasibility of the proposed research is increased by the existence of clinical specimens, data, and CT scans
from a recently completed large (138 aPAP patient) randomized, double-blinded, placebo controlled clinical GM-CSF
therapy trial, which are available to us. In Aim 1 we will evaluate DBSC-GMAb test kit for diagnosis of aPAP and EC50-
GM-CSF Test for predicting the dose of GM-CSF patients will require as therapy of aPAP. In Aim 2, we will determine the
kinetics by which GM-CSF regulates cholesterol (and surfactant) clearance by AMs and the role of ABCG1 and STAT5 in
this mechanism. In Aim 3, we will evaluate several pathogenesis-related biochemical and radiological outcome measures
of PAP disease severity and treatment responses. Expected results will validate a new test to accelerate and improve the
diagnosis of aPAP, evaluate a test to determine the GM-CSF d...

## Key facts

- **NIH application ID:** 9971986
- **Project number:** 2R01HL085453-14
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Bruce C Trapnell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $397,500
- **Award type:** 2
- **Project period:** 2007-04-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971986

## Citation

> US National Institutes of Health, RePORTER application 9971986, Pathogenesis-Based Diagnostics and Pharmacotherapeutics for PAP (2R01HL085453-14). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9971986. Licensed CC0.

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