Genetically Modified Virus to Kill Rescue Girl Bacteria with Antibiotic Resistant Infection | Science

A week after the 15-year-old cystic fibrosis patient aged Helen Spencer had a double lung transplant in September 2017, the incision wound turned bright red. Isabelle Carnell fought for half of her life against a drug-resistant infection. Mycobacterium Abcessusand now he was spreading rapidly, bursting into crying wounds and swollen nodules through his fragile body. "My heart squeezes when I see that one [lung transplant] The patient has a wound infection because I know what will be his trajectory, "says Spencer, Isabelle's respiratory pediatrician at Great Ormond Street Hospital in London. It's a tortuous journey that has resulted in the death of all these children. "

As standard treatments failed, Isabelle's mother asked Spencer for alternatives – adding that she had read something about the use of viruses to kill bacteria. Spencer decided to focus on what seemed like a crazy idea: phages, viruses that can kill bacteria, and have a long history, albeit verified, of medical treatment. She collaborated with leading phage researchers, who concocted a cocktail of the first genetically modified phage ever used as a treatment – and the first intended for a mycobacterium, a genus that includes tuberculosis (TB). After six months of custom-made phage infusions, Isabelle's injuries have healed and her condition has improved without serious side effects, report the authors today. Nature Medicine.

"It's a convincing proof of concept, even if it's just one case study," says Eric Rubin, researcher in infectious diseases, from Harvard TH Chan School of Public Health in Boston. But, he adds, "this must be rigorously tested with a real clinical trial".

Phage therapy dates back a century, but until recently, the idea was relegated to the rank of marginal drug in most countries, mainly because of the arrival of antibiotics. Unlike broad-spectrum antibiotics, individual phages usually kill a single bacterial strain, meaning that a treatment that works against one's infection can fail in another person infected with a variant of the same bacteria. Phages can also be toxic. But a series of recent successes against antibiotic-resistant bacteria has revived interest in this idea, prompting major American universities to launch phage research centers. Drug-resistant TB strains are a particularly attractive target for phage therapy.

Mr. Abcessus and other bacteria often colonize the thick mucus that builds up in the lungs of people with cystic fibrosis, a genetic disease that affects around 80,000 people worldwide. Infections can lead to serious lung injury, for which a transplant is a last resort. Isabelle, for example, had lost two-thirds of her lung function. But his infection persisted after the transplant, threatening his life.

To help Isabelle, Spencer's team contacted Graham Hatfull, a phage researcher, from the University of Pittsburgh, Pennsylvania. Hatfull and his team are organizing a collection of more than 15,000 phages, one of the largest in the world, many of which have been discovered by undergraduate students in more than 150 schools participating in a phage hunting educational project. Hatfull and his team spent 3 months looking for phages that can kill Mr. Abcessus isolated from the wounds and sputum of Isabella. They found three.

Hatfull's group wanted to combine the phages in a cocktail to reduce the risk of Mr. Abcessus develop resistance, but there was a trap. Two of the three are so-called temperate phages, which possess repressor genes that limit their lethality. To turn these two viruses into reliable bacteria killers, Hatfull removed the repressor genes with a gene modification technique developed by his laboratory to study phage genetics.

Isabelle received for the first time an infusion of the phage cocktail in June 2018. In less than 72 hours, her wounds began to dry out. After 6 weeks of intravenous treatment every 12 hours, the infection had almost disappeared. Traces remain however, so she still receives infusions twice a day and applies the treatment directly to her remaining lesions. But she leads a more normal teenage life, goes to school, shops with friends and takes driving lessons. "We are optimistic that over time this will completely erase the infection," Spencer said.

Spencer, Hatfull and his co-authors point out that Isabelle could have improved without phage treatment. They also note that his tailor-made cocktail does not work against others Mr. Abcessus isolates they tested. Nevertheless, apparent success has encouraged phage researchers. Other phages of the Hatfull library infect and kill M. tuberculosis in test tubes, and he thinks that they could be useful weapons against drug-resistant strains.

But William Jacobs, a TB specialist at the Albert Einstein College of Medicine in New York, tested these phages in a murine tuberculosis model and found no effect. "Tuberculosis lives inside cells and I do not think phages can penetrate inside," says Jacobs. (Mr. Abcessus mostly live outside the cells.) Others say there may be ways to introduce phages into the infected cells.

The phage processing companies have at least three ongoing trials to rigorously evaluate the value of their potential products for several bacterial infections. Even if the treatments are successful, they face great practical obstacles, says Madhukar Pai, an epidemiologist at McGill University in Montreal, Canada. "For this to become a real-world therapy, we need to know if we can do it with less effort and cost."