While proper diagnosis is key to effective TB treatment, there exist specific barriers to TB testing in low resource settings, especially for children. While a number of TB diagnostic tools are available, they each suffer from critical drawbacks (difficult, inaccurate, expensive) that limit their widespread implementation in low resource settings and their feasibility in children. A mycobacterial cell wall glycolipid, lipoarabinomannan (LAM), as a diagnostic pathogen biomarker has been widely demonstrated and one point-of-care (POC) LAM assay (Alere Determine? TB LAM) is currently on the market. Alere?s technology incorporates LAM detection in a urine-based lateral flow assay (LFA) and while easy to use, its poor diagnostic sensitivity limits its utility to patients with extremely high LAM concentrations (e.g., patients with advanced HIV disease and CD4 counts <100). This limitation is particularly problematic in children, given their higher incidence of paucibacillary TB (when LAM concentration is likely even lower). In this study we will bridge the gap between the unmet need for TB diagnostics in children and the use of LAM as a promising solution by applying an emerging technology, termed ?FLOW?, to enhance the sensitivity of the LAM LFA. While the Alere LFA measures LAM from only a few droplets of urine, FLOW concentrates LAM from several mL of urine into ~100 L, which is then assayed by the LFA. Importantly, FLOW concentration is completely passive, requiring little or no additional steps beyond LFA-based analysis, thus making it a simple and user friendly ?front end? for LFAs, especially within low resource settings where TB is most prominent. As proof of principle, in a small, adult only, first-in-human (FIH) study performed in South Africa (funded by the Bill and Melinda Gates Foundation, see letter of support), running FLOW-concentrated urine on Alere and (our newly developed) Salus LFAs resulted in doubling of clinical sensitivity. In this FastTrack SBIR proposal we will optimize and adapt FLOW for the diagnosis of TB in pediatric patients by:
In Aim 1, optimizing the FLOW technology to maximize analytical sensitivity among children with TB;
In Aim 2, assessing clinical sensitivity in a small, pediatric only, pilot study performed at our partner clinical research site in South Africa;
In Aim 3, implementing necessary changes and/or improvements as needed and develop an improved collection-to-answer workflow for our device, including furthering the development the Salus LFA. Additionally, we propose to develop a ?wearable? adaptor, geared toward the very young (e.g. ages 0-4) and very sick, that will plug into our FLOW workflow and allow for efficient sample collection and assessment of patient TB status; and in Aim 4 employing our FLOW TB assay back to South Africa for a properly powered study, the results of which will provide a foundation for our route to commercialization (Aim 5). Importantly, we have already identified partners (Abbott Laboratories, Intuitive Biosciences, see letters of support) to complete the commercialization process if the data from the proposed work is promising.

Public Health Relevance

Proper diagnosis is key to effective tuberculosis (TB) treatment, but there exist specific barriers to effective TB testing in low resource settings, especially in children. Thus, the goal of this project is to adapt our current point-of-care (POC) TB diagnostic assay to be sensitive enough for use in children, who often present with paucibacillary disease. Specifically, we will perform assay optimization and a small-scale pilot study of clinical sensitivity in Phase I that will evaluate the overall effectiveness of our assay technology, informing the next iteration of improvements prior to larger pediatric study in Phase 2.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
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Special Emphasis Panel (ZRG1)
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Majji, Sai Prasanna
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Salus Discovery, LLC
United States
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