Phage treatment for non-tuberculous mycobacterium infection after lung transplant

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After British 15-year-old Isabelle, who has cystic fibrosis (CF), received a double lung transplant at Great Ormond Street Hospital in London, her non-tuberculous mycobacterium (NTM) infection returned and spread extensively throughout her body. As a last resort treatment her mother contacted researchers at the University of Pittsburgh in the USA about the possibility of Isabelle receiving an experimental ‘phage’ treatment to help kill off the infection and save her life. The researchers agreed to help, developing a cocktail of three phages that targeted the very specific strain of NTM causing the infection. After receiving the treatment, Isabelle’s condition improved dramatically. Here we explore the story behind the headlines.

What is NTM?

NTM, or non-tuberculous mycobacterium, is a collective name for a group of bacteria that some people with CF develop in the lungs. People can become infected with a particular strain of NTM, and some of these strains may be more harmful than others. The most common bacteria within the NTM group is known as Mycobacterium abscessus (M. abscessus). M. abscessus is extremely difficult to treat in people with CF, requiring long periods of taking strong antibiotics.

If people are being considered for a transplant, whether or not they have NTM will be taken into account during these discussions, as NTM could affect the outcome of the transplant. The immunosuppressant drugs that people take post-transplant to prevent the body ‘rejecting’ the new organ will also make them more susceptible to infection. Even if NTM has been treated, it is possible the infection might recur after transplant.

What are bacteriophages or ‘phages’?

Isabelle was treated with a cocktail of bacteriophages. Bacteriophages, sometimes abbreviated to ‘phages’, are viruses that can attack and destroy bacteria. While they’ve been known about for nearly 100 years, they haven’t been used very much in modern medicine, as antibiotics were an effective way of treating bacterial infections. However, with increasing antibiotic resistance, researchers are looking into their potential again.

Bacteriophages are very choosy in which bacteria they attack. When Dr Hatfull and his team at the University of Pittsburgh agreed to help develop a treatment for Isabelle, they had to systematically test each of a ‘library’ of over 15,000 different types of bacteriophage to see if they might work against Isabelle’s specific strain of NTM, which was grown in their labs from a sputum sample provided by Isabelle.

They found three phages that could target the strain she was infected with, and the next step was to check that the phages could successfully kill the bacteria. They found that two out of the three phages were fitted with the genetic equivalent of a ‘safety catch’. With a gun, when a safety catch is on, the gun can’t be shot. The same is the case for these two phages; when the genetic safety catch in in place, the phage can’t do its job of killing bacteria. Dr Hatfull and his team used gene editing to remove this safety catch, which meant all three types of phage were able to effectively kill the bacteria.

The Trust has already funded some very early research in this area as a possible new way to treat another lung infection, Pseudomonas aeruginosa. However, they may have other uses too - researchers at Manchester Metropolitan University are using them as a potential method to detect the presence of Pseudomonas.

What does this mean for people with CF with NTM infections?

Isabelle’s health improved once she was treated with this hand-picked cocktail of three bacteriophages. It was the first time that a bacteriophage treatment had been used for an M. abscessus infection and was also the first time that a genetically edited version of a bacteriophage had been used as a treatment.

However, the researchers point out in their report while it appears that it was the treatment that led to the improvements, more studies are needed before scientists can be sure that this is the case. A way to test this would be to run a clinical trial of phage therapy. We are not aware of any such clinical trials being planned.

Dr Hatfull’s lab have gone on to test the cocktail of phages included in this treatment against other strains of NTM, and found that they do not kill them. However, there may be other phages in his 15,000-strong collection that do. This highlights another practical problem - currently it is a slow and labour-intensive task for researchers to find and test phages that may be effective against many different strains of bacterial infections.

 “What these researchers, and Isabelle and her family, have shown is that this treatment approach is possible. But we still need as many different ways as possible to tackle this infection. NTM is recognised by people with CF as a key topic for research, as it is so difficult to treat”, said Dr Janet Allen, our Director of Strategic Innovation.

“The Trust has been investing in research to develop new drugs to combat antibiotic resistance, such as our Innovation Hub on lung health and our Strategic Research Centre that is looking to develop new treatments for NTM.”

“This new report opens the possibility of another tool in our armoury against NTM. While Isabelle’s story is a single case report, it lays down a challenge to scientists and clinicians to rigorously test this approach, and to establish whether the findings are more widely applicable not only to NTM but to other antibiotic-resistant bacteria.” 

The results of this research were published on 8 May in Nature Medicine (Dedrick et al) , and you can ready a commentary of the research in Science magazine.

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