BX004-A: development of an anti Pseudomonas aeruginosa phage cocktail by BiomX
Cystic fibrosis (CF) is a recessive genetic disease, caused by the inheritance of two mutated alleles of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR is an epithelial anion channel involved in homeostasis by transporting chloride and bicarbonate across the membrane. Properly functioning CFTR maintains epithelial surface hydration, thus repelling bacteria and supporting proper unfolding of mucins in the lungs. An array of mutations in the CFTR gene alter or completely abolish the activity of this channel, thus causing buildup of thick mucus layers in the lungs. The main cause for morbidity and mortality in CF patients is chronic pulmonary infections, caused by antibiotic-resistant bacteria that thrive in such conditions. The most prominent pathogen associated with CF is Pseudomonas aeruginosa, which infects roughly half of adult CF patients, according to the 2020 Cystic Fibrosis Foundation Patient Registry Annual Data Report. P. aeruginosa is a potent pathogen which inflicts severe lung damage by secreting an array of virulence factors. Standard of care treatment for P. aeruginosa infections includes cycles of antibiotic treatments, namely aztreonam and tobramycin. However, over time antibiotic resistant P. aeruginosa strains become abundant and impede the effectiveness of treatment, thus leading to acute outcomes.Bacteriophage (phage) are viruses that target and infect specific bacterial strains. Lytic phages then exploit the bacterial cell resources for propagation and finally lyse the bacterium to free their progenies and allow them to seek additional bacterial targets. Since the mechanism in which phage destroy bacteria is orthogonal to that of antibiotics, they are considered a promising medical tool to combat antibiotic resistant bacteria. Phage administrated to CF patients in the context of compassionate treatments have been showing positive signs. First, no phage-related adverse events were reported, thus further validating the overall safety of phage. Subsequently, positive clinical outcomes - such as improvement in forced expiratory volume in the first second (FEV1), reduction in bacterial burden, and increase in body mass index were observed for some patients who received phage. While these are important pioneering endeavors, compassionate treatments are inherently limited in scope and interpretability, due to the personalization of the treatment and the lack of a control group. In this work, we set out to develop a broad anti-P. aeruginosa phage cocktail that will fit a large population of CF patients and test it in a double blinded placebo controlled clinical trial.