Pathogenesis-Based Diagnostics and Pharmacotherapeutics for PAP

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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 dose patients require as therapy aPAP, determine if GM-CSF therapy should be administered daily or on alternating weeks, and validate new outcome measures of lung disease and treatment responses in aPAP. These expected results are anticipated to have significant positive impact because they are expected to lead to improved healthcare delivery by practicing physicians, improve the quality of life for people living with PAP, and accelerate the pharmacotherapeutic development of GM-CSF as a new treatment for aPAP patients.