Enabling comprehensive diagnosis of sub-acute infection in chronic respiratory disease via high sensitivity next generation sequencing

ABSTRACT
Sub-acute lung infections are increasingly recognized as drivers of poor symptom control among a subset of
individuals with chronic lung disease (estimated more than 2 million for Asthma and COPD patients). When
these sub-acute infections are diagnosed and treated appropriately, chronic lung disease patients can convert
from moderate/severe to a milder disease phenotype, requiring lower medication to achieve better health at a
significantly lower cost. Current gold-standard diagnostics for sub-acute infection rely on decades-old
technology that can take weeks to complete, have limited sensitivity, and are limited in the type and number of
microbes that can be screened by a single test. Thus, a critical gap exists due to the inability of current
diagnostics to comprehensively, quickly, and accurately detect microbial pathogens in low-burden clinical
samples, which is a significant barrier to improved clinical outcomes in chronic lung disease. We developed a
comprehensive NGS targeted amplicon panel for a) detection and profiling of microbes with associated
treatment resistance data and b) profiling human immune system host response genes. Our NGS diagnostics
(Dx) panel is a significant technological innovation over current methodology due to the combination of the
inherent technical characteristics of a targeted NGS approach, the specific set of amplicons we target and our
proprietary laboratory and analysis workflows. The long-term goal of this project is to provide a novel clinical
tool for the detection of low-burden microbial infections driving disease pathology, symptomology, and
exacerbations in chronic lung disease populations such as COPD, cystic fibrosis, and moderate to severe
Asthma. Our preliminary studies demonstrate an ability to a) utilize patient samples directly vs. requiring
cultures, b) provide orders of magnitude greater sensitivity and accuracy than qPCR or metagenomic
approaches, and c) comprehensively screen bacterial, fungal and viral species in a single assay. Our specific
aims are designed to test the feasibility of our NGS Dx approach to provide substantial enhancements in
accuracy, sensitivity, specificity, and speed over current clinical standards. The first aim of this study is to
establish the limits of detection and specificity of the targeted NGS Dx panel to detect microbial species when
most of the DNA/RNA in the sample comes from a human host. The second aim of the study is to demonstrate
the feasibility of the NGS Dx panel to identify sub-acute infections among subjects with severe chronic lung
disease. After successful completion of these aims, Phase II studies will build off of these and other early
research activities to demonstrate clinical validation and utility in a CLIA certified laboratory, enabling
engagement of patient samples for clinical diagnostic testing. The total market for this diagnostic is the set of
chronic lung disease patients with uncontrolled symptoms who could be screened for sub-acute infections.
Our competitive advantages include vastly improved sensitivity, speed, comprehensive microbe detection,
microbe profiling, stream-lined analysis, and treatment effectiveness insights within a single assay.PROJECT NARRATIVE
Low-level lung infections that do not exhibit the usual symptoms of a pathogen can be a major source of
uncontrolled disease in patients with certain lung conditions, like asthma and COPD. Patients with uncontrolled
disease experience significant medical costs, hospitalizations and negative impact on quality of life. The goal of
this STTR is to evaluate the accuracy of a new diagnostic test for low-level lung infections in patients with a
chronic lung disease, thereby providing treatment guidance to achieve disease control for the patient
!