Phage Therapy--Promising Treatment for Lung Disease?

The bacteriophage, also known as phage, is a virus that kills bacteria. There are more phages than any other organism on earth and they are easily found and retrieved from ponds, lakes and the ocean. It is hard to believe but 40% of the bacteria in the ocean is killed by phages every day!

The phage looks like a microscopic land rover sent to explore another planet.  Its twenty-sided head sits on a tail that has leg-like fibers attached to it.  Each phage has the genetic makeup to destroy a specific bacteria. It uses its tail to puncture the host and inject its own genetic material into it, thereby turning the bacteria into a phage factory. When the bacteria is full, the phage manufactures a substance called endomycin to punch a hole in its host and release the newly made phages.

Phages were identified by English bacteriologist Fredrick Twort in 1915 and French Canadian scientist Felix D’Herelle in 1917.  D’Herelle realized that they could be used as antibacterial agents and over the years advanced his research by opening phage therapy centers throughout Eastern Europe. However, with the discovery of the miracle drug—penicillin-- by English scientist Alexander Fleming in 1928, interest in phage therapy decreased, especially in the West.

Now, one hundred years later, the tide is turning and there is renewed interest in bacteriophage therapy. This interest is mainly due to the mutation of bacteria and fungi and the creation of Antibiotic Drug Resistant (ADR) superbugs caused by the overuse of antibiotics.  According to the Center for Disease Control, close to three million people a year in the United States get ADR infections and 35,000 die from them. Unfortunately, the need for new antibiotics is not being met by the pharmaceutical industry. A recent report by a roundtable of experts stated that “if no immediate action is taken, the estimated death toll due to antimicrobial resistance will reach the millions by the year 2050”. (1)

I first learned about phage research and therapy when I attended a NTM and bronchiectasis patient symposium a couple of years ago at Yale University in New Haven, Connecticut. Subsequently, I heard phage therapy brought up at a New York University Bronchiectasis and Non-Tuberculous Mycobacteria Symposium and more recently, last month at the 4th World Bronchiectasis Conference. 

Nonetheless, what really piqued my curiosity was an online support group post by Daniel, a young Canadian man who had Pseudomonas Aeruginosa (PA). Daniel was experiencing chest pain and struggling with shortness of breath and lung congestion. Even though he was taking an antibiotic, his symptoms persisted. His father, after seeing a documentary on phage therapy, suggested to Daniel that it might be an option. After research, Daniel chose the Eliava Institute Phage Therapy Center  in Tbilisi, Georgia for his care. He sent them a sputum sample and they created a phage cocktail specifically for him. Over a two-month period, with two breaks from treatment, he drank his phage solution and nebulized it.

This month I checked in with Daniel to see how he was feeling. With his treatment practically completed, he told me that his condition had improved quite a bit since beginning the phage therapy. Before the therapy he did not have the energy to exercise much and now he was able to use his elliptical exercise machine for 20 minutes a day. He was also happy to share with me that his latest sputum analysis did not show any Pseudomonas.

More and more academic institutions and businesses are creating phage libraries and synthetic phages in the United States as well as around the world. Looking at phage therapy in contrast to antibiotics, we can more clearly see the pros and cons of this therapy that is now gaining attention:
 
Advantages of Phage Therapy Over Antibiotics

• They are specific to a particular bacteria or family of bacteria, therefore phages do not kill good bacteria and compromise the individual’s immune system.
• If a bacteria becomes resistant to a phage, there are abundant phages in the environment to test to see whether another one can substitute.
• Antibiotic resistance does not imply phage resistance. In fact, in some cases, phages can make a bacteria that was previously resistant to an antibiotic, less resistant.

 
Disadvantages of Phage Therapy Over Antibiotics

• It is more difficult for phages to kill bacteria that are intracellular such as mycobacteria infections
• Possibly impurities in the phage solutions could cause septic shock. This can be addressed in the phage therapy preparation process but it is still a potential issue.
• There are hurdles regarding the FDA, EMA and other worldwide regulatory agencies. A natural occurring substance is not considered intellectual property that can be protected legally. However, many of these phage therapy preparations are engineered or partially engineered and could be considered intellectual property. Additionally, the need to regularly modify phage cocktails with new phages to control resistance further complicates this issue.

 
The good news is that finally there are several high-quality, controlled studies set to begin. They will test the efficacy of phage therapy, mainly addressing bacterial infections in the Cystic Fibrosis population. We are wading into a new era of quality data and I look forward to seeing the results and whether phage therapy is efficacious for the broader lung disease population.

CYstic Fibrosis bacterioPHage Study at Yale (CYPHY)
Clinicaltrials.gov Identifier: NCT04684641
Phase:2
The primary objective is to see whether YPT-01 phage therapy reduces sputum bacterial load in cystic fibrosis with Pseudomonas aeruginosa
Sponsor: Yale University
Collaborator: Cystic Fibrosis Foundation
Start Date: December 2020
Estimated Completion Date: December 2021
Contact: Jonathan Koff, Yale University

Evaluating Safety and Tolerability of Inhaled AP-PA02 in Subjects With Chronic Pseudomonas Aeruginosa Lung Infections and Cystic Fibrosis (SWARM-Pa)Clinicaltrials.gov Identifier: NCT04596319
Phase: 1b/2a
Single and multiple ascending dose study to evaluate the safety, tolerability and phage recovery profile of AP-PA02 multi-bacteriophage therapeutic candidate administered by inhalation in subjects with cystic fibrosis and chronic pulmonary Pseudomonas aeruginosa (PA) infection.
Sponsors and Collaborators: Armata Pharmaceuticals, Inc. and Cystic Fibrosis Foundation
Estimated Start Date: December 2020
Estimated Completion Date: March 2022
Contact: Vicki White, BS310-633-4566vwhite@armatapharma.com
Contact: Pierre Kyme, PhD310-665-2928 ext 234pkyme@armatapharma.com
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 #bronchiectasis #phage #phagetherapy #pseudomonas 
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(1) ncbi.nlm.nih.gov/pmc/articles/PMC6023077/