Personalizing viral phages to fight drug-resistant infections

The Howard Hughes Medical Institute and the University of Pittsburgh started a program called SEA-PHAGES in the 1990s that offered college students an opportunity to hunt for bacteria-killing viruses known as bacteriophages. At the time, the researchers heading up the project didn’t expect to be able to turn the phages into therapeutics. But that’s exactly what they did, much to the benefit of a 15-year-old girl.

That patient, who was treated at London’s Great Ormond Street Hospital, had cystic fibrosis and had just undergone a double lung transplant. But then doctors noticed signs of infection in her liver, and nodules of bacteria started popping up across her body that traditional antibiotics failed to contain.

A team led by Howard Hughes researcher Graham Hatfull used phages in the SEA-PHAGES collection to specifically target the bacterial strains found in the girl. After six months, nearly all of her skin nodules disappeared, her surgical wound started healing and her liver function improved, the team reported in the journal Nature Medicine.

“The idea is to use bacteriophages as antibiotics—as something we could use to kill bacteria that cause infection,” Hatfull said in a statement. Such engineered phages could offer a personalized approach to treating drug-resistant bacteria, the researchers figured.

More than a nonillion phages—that’s 1 followed by 30 zeroes—exist in our environment. The SEA-PHAGES program, led by Hatfull, has amassed what he says is the world’s largest collection of phages, which have been gathered from thousands of different locations around the world by more than 20,000 students in the past decade. The phages fill about 15,000 vials in Hatfull’s lab.

Collecting as many phages as possible from dirt, water and air is just the first step. Because responses differ among phages, the researchers then had to examine each phage under a microscope, sequence its genome and test its ability to fight bacteria.

After receiving samples from the cystic fibrosis patient, the team determined the infection was caused by a drug-resistant strain of Mycobacterium abscessus. Hatfull and colleagues screened their collection on lab dishes to find the right phages to target the bacteria. They tested individual phages known to infect relatives of the patient's strain, as well as mixed combinations of thousands of other phages.

Three phages—Muddy, ZoeJ and BPs—were picked. Muddy is the most effective, the researchers found. To make ZoeJ more powerful, the team edited its genome, removing a repressor gene that lets it reproduce harmlessly in a bacterial cell. Without the gene, ZoeJ was able to multiply and kill the cell. As for BPs, the team managed to isolate mutants with single-base changes that also led to efficient infection control.

The team administered a cocktail of the three phages intravenously. The treatment helped eliminated the infection in the girl’s liver after six weeks without causing any serious adverse reactions, the researchers reported. Only one or two skin nodules remain now, they added. What’s more, the bacteria haven’t developed resistance to the therapy, and Hatfull’s team is preparing to add a fourth phage.

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Using phages to fight bacteria is an idea that has been around for a century, but until recently, confirmed scientific data in the clinic on safety and efficacy have been limited. Interest in phages has ramped up lately amid the rise of antibiotic resistance.

Several biopharma companies have started researching phages as antimicrobial treatments. Johnson & Johnson recently partnered with Locus Biosciences, which is using the gene editing system CRISPR-Cas3 to develop drugs against bacterial pathogens. Israeli company BiomX recently raised $32 million in a series B with bigwig backers such as OrbiMed, Johnson & Johnson Innovation and Takeda Ventures. The company’s initial focus is on phage cocktail therapies that target antibiotic-resistant strains of Propionibacterium acnes and inflammatory bowel disease. French biotech Pherecydes Pharma is also working on phage-based therapies that target Staphylococcus aureus and Pseudomonas aeruginosa.

The FDA has publicly endorsed the development of phage therapies. In a workshop on phage therapy in July 2017, Doran Fink, an official with the FDA’s Center for Biologics Evaluation and Research, said the industry should “initiate scientifically rigorous clinical development programs that include adequate and well-controlled clinical trials to support licensure of phage therapy products” and that the agency "is prepared to assist developers of phage therapy products in addressing this challenge,” according to a transcript (PDF) of the meeting.

Hatfull’s study showed genetically engineered phages could be customized to each patient, though finding the right phages could be challenging. He suggests scientists may be able to develop phage mixtures that work more broadly in diseases such as P. aeruginosa, a bug commonly found in burn victims.