Project 2 - Nanomaterials for treament of infectious lung diseases
Project Leader - Carolyn L. Cannon, M.D., Ph.D.
The goal of this Project is the development of multi-functional, biodegradable NPs optimized for loading of both antibiotics and inhibitors of antibiotic resistance and targeting for localization of antibiotics and diagnostic imaging moieties to lung infections.
Rationale. Pulmonary infections remain a global health issue with pneumonia representing the leading cause of death due to infection in children under the age of five, according to the World Health Organization. Among adults, tuberculosis (TB) is the leading cause of death from a treatable infectious disease resulting in approximately two million deaths annually. Treatment strategies have been complicated by emergence of drug resistant strains of Mycobacterium tuberculosis (MTb). Similarly, emergence of resistant strains of bacteria complicates treatment of lung disease in patients with cystic fibrosis (CF), the most common life-shortening genetic disease among Caucasians. Over 95% of CF patients succumb to respiratory failure due to lung infections with multiple species, particularly Pseudomonas aeruginosa (PA) CF results from mutations in the CF transmembrane conductance regulator (CFTR) and affects about 70,000 worldwide. Based on definitions from the FDA, CF constitutes an orphan disease. We aim to develop novel NP delivery systems for treatment of TB- and PA-mediated CF lung disease. Systems designed to treat infections in CF patients will allow for an accelerated review process through the FDA and serve as precedent for review of analogous systems developed to treat TB. Finally, our approach may be generalizable to allow development of nanosystems to treat multiple pulmonary infectious diseases.
Hypothesis and Specific Aims. We hypothesize that high local concentrations of antibiotics targeted directly to the pulmonary pathogen and accompanied by inhibitors of bacterial antibiotic resistance determinants will accelerate eradication of MTb and PA. Therefore, we propose the following specific aims:
- Optimization of antimicrobial efficacy. Development and evaluation of NPs optimized for dual-loading of antimicrobials and inhibitors of antimicrobial resistance determinants.
- Targeted delivery. Development and evaluation of targeting strategies to optimize antibiotic release in areas of infection and tracking strategies for antibiotic-loaded NPs through non-invasive imaging techniques for diagnostic purposes.
Path to IND. The most promising diagnostic or therapeutic candidates will undergo preclinical testing prior to a pre-IND conference with the FDA to detail the subsequent studies necessary to apply for IND status. Additional funding will be obtained to perform large animal studies and any other studies suggested by the FDA in the pre-IND meeting. Our goal in this project is to identify nanosystems of potential clinical utility and gather sufficient proof of the utility to warrant a pre-IND meeting. As noted above, because CF is an orphan disease, systems designed to treat Pseudomonas infections in CF patients will receive an accelerated FDA review and serve as precedent for review of antitubercular systems.