PI’s: Andres Garcia
Cystic fibrosis (CF) is a life-threatening, inherited chronic disease that affects the lungs and digestive system of 30,000 children and adults in the US. Lung disease results from clogging of the airways due to mucus build-up, chronic inflammation, and bacterial infection. Bacterial infection, including by Pseudomonas aeruginosa and Staphylococcus aureus, is the main causative agent of morbidity and mortality in CF patients. For the treatment of CF-associated infections, antibiotics represent the standard approach. However, the efficacy of antibiotics is severely limited by dosing and development of multi-drug resistance, and many of the current antibiotics are ineffective in eradicating the bacteria once chronic infection is established. Therefore, there is a significant and urgent need for the development of new strategies that can deliver anti-microbials in a targeted fashion to eradicate bacterial infections in the CF lung.
The objective of this project is to engineer biodegradable polymeric microparticles (MPs) delivering active bacteriophage (phage) to reduce CF-associated infections. Our hypothesis is that phage-presenting MPs (phage-MPs) will be efficiently delivered to the infected airway where the phage will infect and kill bacteria to eradicate the infection. We have formulated this hypothesis based on the ability of lytic phage to infect and destroy bacteria, but not mammalian cells, and our expertise in engineering bioactive biomaterials for delivery. Although phage have been explored to reduce CF-associated infections [1-3], their use is severely limited by the inability to deliver active phage to the deep lung to eradicate infection. In our preliminary work, we engineered biomaterial carriers loaded with phage mixtures with high specificity and activity against P. aeruginosa and S. aureus. We also showed successful delivery of therapeutic doses of phage-MPs via dry powder inhalation to the deep lung and demonstrated significant reductions of bacteria in normal and CF mice. This therapeutic formulation can be translated to conventional, widely used inhalers for increased patient compliance. This research will provide a novel and clinically translatable strategy to eradicate bacterial infections in the CF lung.
Agarwal, R., Johnson, C.T., Imhoff, B.R., Imhoff, B., Donlan, R., McCarty, N., Garcia, A., “Inhaled Bacteriophage-Loaded Polymeric Microparticles Ameliorate Acute Lung Infections”, Nat Biomed Eng 2, 841–849 (2018). https://doi.org/10.1038/s41551-018- 0263-5