NACFC Update: Exciting new methods of Fighting Pseudomonas infection in Cystic Fibrosis!

CFTR modulator data has taken center stage in my Conference blogs so far, but I'm equally excited to summarize some other really interesting talks about new methods to treat Pseudomonas infection in cystic fibrosis.  As we know, chronic infection in the CF lung leads to loss in lung function and bronchiectasis (irreversible widening and loss of elasticity in the airways) over time.  Even if you have an effective antibiotic to treat Pseudomonas, very little medicine is able to penetrate the “biofilm” inside CF lungs to reach the infecting bug.  Think of the  biofilm as an impenetrable layer of super-slime.   When a pathogen enters the CF lung, it finds a nice cozy home in the already thick, sticky CF mucus.  Tissues become inflamed and as cells die, long strands of DNA are left behind, that further bind mucus together.  This makes the environment even more hospitable for bacteria and so the vicious cycle of inflammation, infection, and impaired mucociliary clearance in the CF lungs has begun.   Chronically infected areas of the lungs begin to form these “biofilms” that can eventually cover the entire inside surface of the airways.  Searching for new ways to penetrate the biofilm have yielded some exciting new lines of potential treatments for CF infections.

Before I get into this new research, I want to tell a short story about a job I had in college and I promise it will all make sense in a minute.  One summer I worked with an Entomologist (scientist who studies insects) at WSU.  We worked with local organic farmers to help them eliminate problematic bugs from their crops without using pesticides.  For example, if a farmer had a problem with a particular beetle eating their potato crop, they would hire us.  Our solution was to introduce a different insect to their fields, which didn’t eat potatoes, but absolutely loved eating those problematic beetles.  After the beetles were eaten up, the introduced insects would move on, because their food source would be depleted.  By contrast, if a pesticide had been used to deal with the problem, ALL the bugs in the field would have been killed, even the beneficial ones.  Plus, there would have been a bunch of chemical toxins introduced to the soil and crops.  This natural method of pest control made a lot of sense to me.  Now back to Pseudomonas…

Abstract 270: Rational Design of a Pseudomonas Aeruginosa Bacteriophage Therapeutic and its Efficacy in a Murine Lung Infection Model.   Presented by David Harper Ph.D

Just as there are countless viruses that can specifically infect humans, there are also millions of viruses in our environment that only infect bacteria—bacteriophages.  Bacteriophages are already present in our bodies by the trillions and are completely harmless to us.  They can only survive if they are able to infect a “host bacteria.”  Bacteriophages kill their host immediately upon infection.  Bacteriophages are also host specific, which means there are certain varieties that only infect Pseudomonas aeruginosa (Pa).  I certainly like the idea of tiny Pseudomonas assassins (trigger 007 theme music)!  This line of research explores whether using a bacteriophage cocktail specific for Pa might be an effective way to treat chronic Pa infection in the CF lung.  The investigator used 3 Pa specific bacteriophages in his “killing cocktail” and administered the treatment to mice infected with Pa.  What he found was really amazing.  Unlike antibiotics, bacteriophages easily penetrated the biofilm.  They proceeded to infect and kill the Pseudomonas, and even disrupted and disseminated biofilms.  Because bacteriophages have no interest in infecting anything besides their specific target, there was no collateral damage to the airway tissues.   In the mice, it was shown to be an extremely effective at killing Pseudomonas previously THRIVING in the biofilm.  For a bacteriophage, visiting a biofilm is sort of like going to an “all you can eat buffet.”  They love it!  There are bacteriophages specific to both mucoid and non-mucoid strains of Pseudomonas, so I guess what I’m saying is—You’d better keep both eyes open Pseudo…there might be a new bug getting introduced into the potato field!  I think the guy who came up with this idea is a freaking genius and I sincerely hope we can see something like this translate to human infections in the near future.  There are plenty of negative issues surrounding chronic antibiotic use, including: bacterial resistance, unpleasant side effects, ineffectiveness because of inability to penetrate biofilm, and more indiscriminate killing of bacteria (they kill the good guys along with the bad guys).  This bacteriophage treatment technique could bring something totally new to our tool kit for treating CF, and might even help solve one of the biggest issues facing the world of medicine right now—antibiotic resistance.  I haven't been able to stop thinking about this research since I watched the presentation...or my summer killing problematic bugs in potato fields! 
 

 

Studies are planned in humans, but no timeline was given yet.  This research was performed by Blake, K.L; Henry, M.; Debarbieux, L.; McConville, M.L.; Prosser, I.M.; Parracho, H.M.; Enright, M.C.; Harper, D.R.  AmpliPhi Biosciences, Bedford, UK and Institut Pasteur, Paris, France. 

A second exciting presentation regarding the fight against Pseudomonas infection was:

Abstract 268: ALX-109 Potentiates the Effect of Tobramycin at Killing Pseudomonas Aeruginosa Biofilms on Human Airway Cells.  Presented by Sophie Moreau-Marquis, Ph.D. 

For reasons unknown to researchers, the iron concentration in the CF lung has been found to be 400x higher than in the non-CF lung.  Iron has been shown to promote the growth of Pseudomonas biofilms on airway cells.  This research looked at the possibility of chelating excess iron in the lungs to allow antibiotics to more effectively battle Pa infection.  Chelation is a process where one chemical combines with another, to render a new stable model that is not reactive (it sequesters, or holds the iron captive so it can’t react with other molecules).  ALX-109 or Alaxia, is an iron-binding glycoprotein, that has recently been granted “orphan drug” status by both the FDA and EMA. 

In the study, ALX-109 was combined with Tobramycin and tested on Pa strains isolated from the sputum of CF patients. The Tobi + ALX-109 combination significantly disrupted biofilms.

It was concluded that an inhalation therapy combining Tobramycin with ALX-109 may be beneficial to CF patients infected with mucoid clinical isolates of Pseudomonas.  This research was conducted by Moreau-Marquis, S.; Stanton, B.A. Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH.  Phase 1 clinical trials are planned.

I love the idea of getting some new powerful weapons to fight CF infections and I encourage anyone interested in participating in clinical trials to sign up for email alerts from the CFF here! http://www.cff.org/research/ClinicalResearch/Find/ClinicalTrialAlerts/

We finally made it home from Orlando this afternoon.  What a long trip from Orlando to Northern Idaho!