# Inhaled DNase as an Adjunctive Tuberculosis Therapy

> **NIH NIH R03** · TRUDEAU INSTITUTE, INC. · 2020 · $99,000

## Abstract

Abstract The central enigma in tuberculosis treatment is the presence of persister cells—a drug
tolerant phenotype characterized by low metabolic activity and very slow rate of growth. To significantly reduce
the burden of tuberculosis, new therapeutic strategies that target persister cells are urgently required. This
proposal suggests a new approach that targets the persistence phenotype by altering an environmental
condition that favors Mtb survival. Specifically, we ask: is there a role for biofilm in persistence in tuberculosis,
and if so, can we disrupt persistence by disrupting the biofilm? We propose to test the hypothesis that in a
mouse model displaying human-like pathology, Mtb persister cells will be present in biofilm-like aggregates on
DNA filaments in the acellular rim of necrotic granulomas, and that treatment of these infected mice with
DNase will disrupt the aggregates and sensitize the Mtb cells to antimicrobial drugs, thereby shortening
treatment time required for a durable cure. Our approach leverages historical strengths of the Trudeau Institute
in mouse models of tuberculosis and advanced imaging technologies. We will utilize an innovative mouse
model that displays human-like pathology to test the hypothesis that Mtb persister cells can be found in
multicellular aggregates on extracellular DNA. We will employ fluorescent bacterial reporter strains that can be
detected even when they lose acid-fast staining, as is typical of Mtb persister cells. In our first aim we setup
and optimize the experimental system and test for the presence of Mtb persister cells associated with
extracellular DNA. Then in aim 2 we will use the optimized system to address the fundamental goal of the
proposal: test the efficacy of inhaled DNase as an adjunctive therapy for tuberculosis. We expect that DNase
treatment will confer a significant benefit in more rapidly reducing bacterial burden than antitubercular drugs
alone, providing justification for clinical testing of this novel adjunctive therapy.

## Key facts

- **NIH application ID:** 9868890
- **Project number:** 5R03AI144706-02
- **Recipient organization:** TRUDEAU INSTITUTE, INC.
- **Principal Investigator:** Brian Weinrick
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $99,000
- **Award type:** 5
- **Project period:** 2019-02-08 → 2021-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9868890

## Citation

> US National Institutes of Health, RePORTER application 9868890, Inhaled DNase as an Adjunctive Tuberculosis Therapy (5R03AI144706-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9868890. Licensed CC0.

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