Journal
MOLECULAR THERAPY-NUCLEIC ACIDS
Volume 22, Issue -, Pages 1121-1128Publisher
CELL PRESS
DOI: 10.1016/j.omtn.2020.10.023
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Funding
- Department of Biotechnology (DBT), Government of India [BT/PR10468/MED/29/815/2013]
- Indian Council of Medical Research (ICMR) [AMR/IN/112/2017-ECD-II]
- Council of Scientific and Industrial Research, India (CSIR)
- ICMR
- University Grants Commission, India
- CSIR
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Nebulized gamma interferon (IFN-gamma) protein has been studied for clinical safety and efficacy against pulmonary tuberculosis (TB). The protein is expensive, requires a cold chain, and is difficult to deploy in limited-resource, high-incidence settings. We generated a preclinical proof of concept (PoC) for a dry powder inhalation (DPI) containing DNA constructs to transiently transfect the lung and airway epithelium of mice with murine IFN-gamma. Bacterial colony-forming units (CFU) in the lungs of mice infected with Mycobacterium tuberculosis (Mtb) reduced from about 10(6)/g of tissue to similar to 10(4) after four doses given once a week. Nodular inflammatory lesions in the lungs reduced significantly in number. Immunohistochemistry of infected lung sections for LC3-1 and LAMP-1 indicated autophagy induction between 18 and 48 h after inhalation. ELISA on bronchoalveolar lavage (BAL) fluid showed differences in kinetics of IFN-gamma concentrations in the epithelial lining fluid of healthy versus infected mice. Uninfected mice receiving DNA constructs expressing a fluorescent protein were live-imaged. The fluorescence signals from the intracellular protein peaked at about 36 h after inhalation and declined by 48 h. These results establish preclinical PoC of the efficacy of a DPI and dosing regimen as a host-directed and transient gene therapy of experimental pulmonary TB in mice, justifying preclinical development.
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