Genetically Modified Viral Cocktail Treats Deadly Bacteria in Teen

Genetically Modified Viral Cocktail Treats Deadly Bacteria in Teen

A team of United States and British scientists are reporting the successful treatment of a life-threatening mycobacterial infection using genetically engineered bacteriophages.

Doctors and scientists stress that it's hard to draw firm conclusions from one patient, whose experience is described in an article in the journal Nature Medicine published Wednesday. That disease is caused by bacterium related to the infection Carnell-Holdaway has. But it's the first using genetically engineered phages.

The place had become an global repository for phages through a program Hatfull had helped develop in which college students around the world isolate and identify phages, learning about biology while expanding knowledge about these viruses that thrive by the trillions within and around us.

To help Isabelle, Spencer's team contacted phage researcher Graham Hatfull of the University of Pittsburgh in Pennsylvania.

The antibiotics had stopped working, and because she was taking immunosuppressive drugs to prevent rejection of the new lungs, her body was unable to fight the bacteria.

Isabelle Carnell-Holdaway, 17, has faced not one but two unrelenting threats to her life.

However, Isabelle, who was born with cystic fibrosis, is now out of grave danger after being given untested "phage therapy". There was also another cystic fibrosis patient at the hospital experiencing the same difficulties.

Luckily, Spencer said, "one of our microbiologist consultants here did his thesis on phage therapy 20 years ago".

Hatfull leads an HHMI program called SEA-PHAGES that offers college freshmen and sophomores the opportunity to hunt for phages.

"Cocktails of phages were used therapeutically in Europe and the United States during the pre-antibiotic era, and they are still prevalent in Russian Federation and Central and Eastern Europe today, for wound infections, gastroenteritis, sepsis and other ailments", wrote Charles Schmidt, a science writer, in a related article published in the journal Nature Biotechnology. Hatfull has spent more three decades building this phage repository. However, it turned out that only one was effective in infecting the targeted bacteria.

The phages infected Mycobacterium abscessus, but tended to live as permanent parasites. "My heart sinks when I see that a [lung transplant] patient has got a wound infection, because I know what the trajectory is going to be", says Spencer, Isabelle's respiratory pediatrician at Great Ormond Street Hospital in London. The treatment relies on genetically engineering bacteriophages, viruses that can infect and kill bacteria.

"I think it's unbelievable", Carnell-Holdaway says.

They found three candidate phages in soil-dwelling mycobacteria that don't infect people.

"We were devastated", says her mother, Joanne.

She is still having two infusions of the viral cocktail every day.

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Unlike previous experiments, the researchers treating Isabelle used genetically modified phages which made them more effective than those occurring naturally.

"We were at the point where there was no other hope, they said she wasn't going to leave the hospital and had less than 1 percent chance of survival."
IV and topical treatment continued at home.

Weeks after the transplant, doctors noticed redness at the site of her surgical wound and signs of infection in her liver. Only one or two of the lesions remain.

Derrick Fouts, a phage expert at the J. Craig Venter Institute in Rockville, Md., said finding the right combination of phages is tricky.

"This is actually a historic moment", Steffanie Strathdee, a professor of medicine at the University of California, San Diego, who was not involved in the study, tells NPR.

According to Hatfull, it was the fact that they had erased part of the viruses' genetic code, without adding anything, that allowed them to get those two phages through regulations on genetically modified organisms and send the live cocktail to London, where it was first used on the patient's external wounds, and then injected into her bloodstream.

Hatfull says he was nervous when it came time for Carnell-Holdaway's doctors to try the cocktail. Around the same time, Jo had been told her daughter was unlikely to survive.

The question is what the future holds for phage therapy, which to date has been used only in individual cases.

This old-time approach to battling bacterial infections might be worth another look in these days of antibiotic-resistant bacteria, a new paper argues.

The phages were introduced into the patient's abdomen and also given intravenously.

"The specificity is definitely our friend in terms of using phages in antimicrobial treatment", Hatfull said.

Companies are now trying to develop phage cocktails - some personalized, some pre-packaged, some natural, some engineered - into biologic drugs. Muddy, ZoeJ, and BPs, for example, don't efficiently kill other M abscessus clinical isolates.

Strathdee, Hatfull and others stress that much more research is needed to determine how well phages, including genetically engineered phages, really might work and how safe they may be.

Patterson said he's still recovering, but "feeling great".

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