Three years ago, Esteban Diaz was advised by doctors to join the lung transplant list after battling cystic fibrosis for most of his life. The disease causes excessive mucus production in the lungs and pancreas, leaving patients extremely vulnerable to bacterial infections. In the case of the 47-year-old Frenchman, the antibiotics that he had been prescribed since childhood were no longer effective against the incessant infections caused by Pseudomonas aeruginosa, a bacterium that is now classified as a superbug.
Diaz not his real name traveled to Georgia, a former Soviet state on the shores of the Black Sea, to undergo phage therapy a medical treatment that he claimed cleared his infections in a few days and killed him. It relieved the nagging fatigue incessant coughing and shortness of breath that plagued him for decades. Bacteriophage viruses are those that naturally take advantage of bacteria by infecting them and replicating within them until they burst, killing their microbial host. There are billions of phages on Earth and they have co-evolved with the bacteria they fed on for millennia, helping to keep their numbers in check. Its therapeutic use was first initiated in 1919 by Felix d’Herelle, a French-Canadian microbiologist who used phages to cure a child suffering from severe dysentery.
However, the discovery of penicillin in 1928 and its subsequent commercial production in the 1940s sparked the age of antibiotics effectively replacing phage therapy. The therapeutic role of phages might have been forgotten had it not been for the collaboration between d’Herelle and George Eliava a young Georgian scientist who had traveled to France in 1923. Eliava arrived to study vaccine development but instead turned her attention to phages after meeting d’Herelle at the Pasteur Institute.
The young man returned to Georgia and invited d’Herelle to help establish the world’s first research institute and therapeutic center dedicated to bacteriophages, just as the country was being taken over by the Soviet Union. Unfortunately, like thousands of intellectuals of the time, Eliava fell out of favor with the Joseph Stalin regime and was executed in 1937. But Soviet sponsorship of therapeutic phage research and development continued at the institute Eliava founded, years after the Western world shelved the approach. Phage therapy was part of the standard medical care system during the Soviet Union says Mzia Kutateladze, director of the Eliava Institute.
Depending on the patient’s health status and the type of infection, doctors would determine whether to use phages, antibiotics, or a combination of both.”However, the institute faced serious difficulties in the years after the disintegration of the Soviet Union. Some researchers resorted to storing phage cultures in their own homes to save them. But soon the institute would play a key role in re-introducing the scope and potential of phage therapy to the world.
It took a long time before people were convinced that phages can be used for therapeutic purposes says Kutateladze. But resistance to antibiotics supports the need to find alternatives he adds. The institute faced enormous challenges when it began presenting its work internationally in the late 1990s. But in 2001 he welcomed his first foreign patient shortly after a conference in Montreal Canadian suffering from osteomyelitis a so-called bacterial bone infection that antibiotics had failed to cure. The treatment worked and thanks to that followed, patients from all over the world began arriving at the Eliava Institute.
Antibiotic Resistance
The World Health Organization (WHO) has called antimicrobial resistance (AMR) a global health crisis and estimates that up to 30 million people will be affected by 2050. For cystic fibrosis patients like Diaz, antibiotic resistance was the inevitable consequence of a lifetime prescription for the drugs. From the age of 7 to 17 every three months, I was systematically bombarded with two different types of antibiotics this was the protocol in the past, Diaz describes. By the time he was 30, he had also developed chronic tinnitus as a side effect of continued use of aminoglycosides the most common family of antibiotics used to treat Pseudomonas infections like yours.
By age 40, resistance had established itself and double lung transplantation was the only option his doctors in France could suggest to prolong his life. After seeing a documentary on phage therapy from the Eliava Institute on a French television channel, he booked a flight. On the fourth day of treatment, it was as if someone had eliminated my disease. I slept through the night for the first time in years. It’s hard to describe I could almost feel the oxygen rushing through my lungs. It was incredible.
Since his first visit, Diaz has regularly returned to Tbilisi to stock up on oral doses of phage preparations that have helped keep subsequent infections under control. That was until it ran out of phages in March this year, just as Georgia closed its borders in its effort to tackle the spread of the coronavirus. As soon as the travel restrictions were eased, Diaz returned for another round of treatment that he said immediately alleviated a persistent cough he had acquired in the meantime.
Problems
But his treatment has not been without complications. Diaz fears losing his benefits if it is discovered that he has traveled to Georgia for treatment, especially during a pandemic. He adds that his personal physicians and a leading cystic fibrosis support group in France have also repeatedly warned patients like him against using phage for treatment, as it is not yet approved for use in Western countries.
But this has not stopped hundreds of foreign patients seeking phage treatments in Georgia, with a handful of specialized medical travel agencies serving them.
French Alain Lavit and his Georgian wife Irma Jejeia have been helping patients like Díaz through their Caucasus Healing agency since 2016. Most of her clients are French, and while some have spoken openly to the media about their phage treatments, Lavit says patients with chronic diseases like cystic fibrosis prefer to remain anonymous due to the complex lifelong relationships they develop with. their doctors in their countries.
It is not illegal to go abroad for treatment, but many of the cystic fibrosis patients we have worked with are concerned about offending their pulmonologists whom they have seen since childhood, and most doctors do not know anything about the therapy. with phages, so they always advise against doing it, “says Lavit. A clause in the French disability pension system, for example, stipulates that patients must seek employment once they recover from their illness, making it difficult for chronically ill people to report any improvement in their symptoms. Phage therapy does not cure them, but it helps their condition,” Lavit adds.
Regulation
Millions of people were treated with phages in the Soviet Union, and the Eliava Institute continues to successfully receive and treat hundreds of international patients each year. But it has been just over two decades since Western scientists resumed research on phage therapy and conducted the necessary clinical trials to regulate their use as therapeutic drugs.
Phagoburn was the first French-led European clinical trial of phage therapy in infected burn wounds following strict medical guidelines. Funded in part with a 3.8 million euro (the US $ 4.6 million) grant from the European Commission, it ran between 2013 and 2017 but was canceled early due to reasons including inability to recruit suitable test subjects and issues on the stability of the prepared phages. Also, it took two years and a significant amount of the project budget to manufacture phages per prescribed Good Manufacturing Practices (GMP).
While the trial showed that phages helped reduce bacterial load in some patients, they did so at a slower rate than the standard treatment. This was a disappointment to proponents of phage therapy including those at the Eliava Institute. It’s not just the failure of a test. it affects the whole concept says Kutateladze, who believes that the type of phage, the prescribed doses and the method of application in the test were not suited to the infection in the patients. It is very difficult to follow the classical standard form of approval. It is not a chemical formula he adds. Phages must match the bacteria they infect for the most effective results, he says.
Medical preparations also need to be regularly updated, making it difficult for them to meet established Western guidelines that were designed for conventional antimicrobials. These are biomedicines and they should benefit from a separate status, especially since they are natural,” says Alain Dublanchat, one of the leading proponents of phage therapy in France, who has often referred patients to the Eliava Institute clinic in Georgia.
For him, the Phagoburn result made it even more difficult for patients like Díaz to speak openly about how phages helped cure their infections in France. The main obstacle seems to lie in the possibility of producing bacteriophage suspensions that satisfy the (French) health authorities,” he says. He adds that the concentration of phages used in the Phagoburn study was also lowered to be on the
Although several developed countries, including the UK, France, and the US, now allow compassionate use of phages on a case-by-case basis, Dublanchet argues that this excludes many people from receiving desperately needed treatment. It seems absurd to wait until people’s lives have reached a precarious stage before we are allowed to (treat) their disease,” he analyzes. Belgium is leading the way as the first developed country to approve the use of phages as magisterial preparations, or personalized medicines that can be prepared by a qualified pharmacist as prescribed by a doctor.
In Belgium, we spent many years arguing with regulators, but this was a mistake says Jean-Paul-Pirnay, director of research at the Queen Astrid Military Hospital (QAMH) in Brussels. Regulators liked phage therapy, but they did not have the power or mandate to change or replace regulations. It was only when the minister of public health officially asked them to help us that the ball began to roll the details.
Pirnay is the author of a document outlining the recommendations for the Belgium Magisterial Phage Medicine Framework, including a regulatory system to create a seed bank of tested and certified phages required for custom preparations. He says there are plans underway to export this solution to the European Pharmacopoeia or a pan-European regulatory solution governing the use of phages, but Covid-19 has slowed the momentum. With these developments, Paul-Pirnay believes that it is only a matter of time before personalized phage therapy is accepted as a standard treatment option around the world.
This is how he described it in “Phage Therapy in the Year 2035”, half scientific article and half science fiction plot that portrays a bleak future “characterized by human overpopulation, major alterations in ecosystems, global warming and xenophobia”, where the Artificial Intelligence helps fight disease by matching the right phages to them. But 2035 is too far away for people who are sick today. Currently, about 700,000 people die each year from RAM infections. Pirnay said the futuristic allegory was inserted into his article to highlight the urgent need for a solution. Although the WHO has repeatedly stated the need to prioritize alternatives to antibiotics, it has never officially mentioned the potential of phage therapy.
There is also a growing demand from phage scientists for WHO to help funnel much-needed funds into more clinical research and testing of phage for therapeutic use. Aside from the regulatory challenges, phages cannot be patented because they are biological products. This has meant that most pharmaceutical companies have avoided funding research to develop them as drugs. Phage resistance bacteria can also develop resistance to phages over time, a problem that phage researchers and doctors have managed to avoid until now.
They do this by isolating new phages from the billions of samples available in nature or by training phages in laboratories to develop new ways to attack bacteria. The latter is a co-evolutionary process that both microbes have been a part of for millennia. New research has identified the defensive immunity called the CRISPR-Cas system that bacteria develop against phages, providing more clues on how to combat potential resistance.
Research laboratories in countries like the US are working on genetically modified phages and the extraction of lysines, the active agent in phages that kill bacteria.
This in turn has sparked the interest of the pharmaceutical giants as these methods can be patented, unlike the natural phages that are currently used for therapeutic use. Last year, Johnson & Johnson signed an initial $ 20 million agreement with Locus Bioscience to research and develop improved Crispr-Cas3-engineered phages that could destroy the defense mechanisms that bacteria develop.
Amid the current buzz of unprecedented modern phage research, the Eliava Institute’s robust and serious work is slowly being overlooked, but its contribution to the current global discussion on phages cannot be denied, says Pirnay, who is jokingly refers to the fact that his team includes two Georgian microbiologists and calls them Eliava Brussels. The Eliava Institute should receive more credit for what it did, but also for what it is still doing he says. Collaboration Since clinical trials for phages in the West are very few and far between, the Eliava Institute has started sharing case studies of its patients online.
Kutateladze hopes this can help others focus their research on more crucial issues. In my opinion, there should be a lot more collaboration he says. A lot of time and money has been spent on details that we have already investigated and documented. The institute is currently collaborating with the Swiss group Ferring Pharmaceuticals and the US company Intralytix to research and develop phages for the treatment of female reproductive health problems.
It is also part of an EU-funded consortium to study the potential use of phages in the treatment of childhood asthma. Meanwhile, the Eliava Institute remains one of the only clinics in the world where patients can receive phage treatments. The clinic recently started online consultation services to help desperate patients unable to travel to Georgia due to COVID-19.
The institute has also been working to upgrade its production facilities to meet good manufacturing practice standards, a challenging task for the institute, often with cash constraints, but which Kutateladze hopes will at some point help facilitate exports. of their medical phage preparations to other countries.
This would be the ideal solution for patients like Diaz. He prefers to travel in-person to Tbilisi to renew his stock of phages and avoid customs intercepting and disposing of them, as has happened in the past when he tried to have them shipped to him by post. That phage therapy is not a readily available treatment is the biggest scandal in modern medicine
