Three years ago, Esteban Díaz was advised by doctors to join the lung transplant list after battling cystic fibrosis for most of his life.
The disease causes a excessive mucus production in the lungs and pancreas, leaving patients extremely vulnerable to bacterial infections.
In this French case of 47 years, the antibiotics that had been prescribed since childhood were no longer effective against incessant infections caused by Pseudomonas aeruginosa , a bacteria that is now classified as a superbug.
Instead, Diaz (not his real name) traveled to Georgia, a former Soviet state on the shores of the Black Sea, to undergo a phage therapy , a medical treatment that he claimed cleared his infections in a few days and relieved him of the nagging fatigue, incessant coughing, and shortness of breath that plagued him for decades.
What are bacteriophages?
Bacteriophage viruses are those that naturally take advantage of bacteria by infecting them and replicating within them until they explode , 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 under control.
Its therapeutic use was started for the first time in 1919 by Felix d’Herelle, a French-Canadian microbiologist who used phages to cure a child suffering from dysentery to severe.
However, the discovery of penicillin in 1928 and its subsequent commercial production in the decade of 1940 unleashed the era of antibiotics , effectively replacing phage therapy.
The therapeutic role of phages could 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.
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Eliava arrived aiming to study vaccine development, but instead turned his attention to phages d fter meeting d’Herelle at the Pasteur Institute.
The young man returned to Georgia and invited d’Herelle to help establish the first research institute and therapeutic center of the world dedicated to bacteriophages , just as the country was being absorbed by the Soviet Union.
Unfortunately, like thousands of intellectuals of the time, Eliava fell out of favor with the regime of Joseph Stalin and was executed in 1937.
But Soviet patronage Research and development of therapeutic phages continued at the institute that Eliava founded, years after the western world dropped the focus.
“L 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 breakup 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 reintroducing them to the world of the scope and potential of phage therapy.
“It took a long time before people were convinced that phages can be used for therapeutic purposes,” says Kutateladze. “But antibiotic resistance supports the need to find alternatives,” he adds.
The institute faced enormous challenges when it began to present its work internationally to late 1990.
But in 1990, received its first foreign patient shortly after a conference in Montreal: a Canadian suffering from osteomyelitis, a so-called bacterial bone infection that antibiotics had failed to cure.
The treatment worked and thanks to a flood of news articles that followed, patients from all over the world began to arrive at the Eliava Institute.
Antibiotic resistance
The World Health Organization (WHO) has classified antimicrobial resistance (AMR) as a global health crisis and estimates that up to 30 millions of people will be affected by the 2050.
For patients with cystic fibrosis such as Díaz, resistance to antibiotics was the inevitable consequence of a lifetime prescription for 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 ”, describes Díaz.
By the time I had 30 years, he had also developed chronic tinnitus as a side effect of continuous use of aminoglycosides, the most common family of antibiotics used to treat pseudomonas infections like yours.
To the 40 years, the resistance had been established and the transplant double of lung was the only option that her doctors in France could suggest to prolong her life.
After watching a documentary about re the phage therapy of 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 “, he details.
Since his first visit, Díaz regularly returned to Tbilisi to stock up on oral doses of phage preparations that have helped to keep subsequent infections in check.
That was until it ran out of phages in March of this year, just as Georgia closed its borders in its effort to address the spread of the coronavirus.
As soon as the travel restrictions were eased, Díaz returned for another round of treatment which, he said, immediately relieved a persistent cough he had acquired in the meantime.
Problems
But his treatment has not been without complications.
Díaz fears losing his benefits if you are found to have traveled to Georgia for treatment, especially during a pandemic.
He adds that his personal doctors and A leading cystic fibrosis support group in France have also repeatedly warned patients like him against the use of 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 such as 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 know nothing about phage therapy, so they always advise against doing so, “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 people with chronic diseases to report any improvement in their symptoms.
“Phage therapy does not cure them, but it helps their condition” , adds Lavit.
Regulation
Millions of people were treated with phage and n the Soviet Union, and the Eliava Institute continues to successfully receive and treat hundreds of international patients each year.
But it has been little more than two decades since Western scientists resumed research on the therapy. with phages and carried out the necessary clinical trials to regulate their use as therapeutic drugs.
“Phagoburn” was the first European clinical trial led by France of Phage therapy in infected burn wounds following strict medical guidelines.
Funded in part with a 3.8 million euro (US $ 4.6 million) grant from the European Commission, it worked between 2013 Y 2017, but it was canceled early due to reasons including the inability to recruit suitable test subjects and stability problems of the prepared phages.
In addition, it took two years and a significant amount of the project budget to manufacture phages. in accordance with prescribed Good Manufacturing Practice (GMP).
While the trial showed that phages helped reduce bacterial load in some patients, they did so at a slower rate than treatment standard.
This was a disappointment to advocates of phage therapy, including those at the Eliava Institute.
“It’s not just the failure of a test… it affects the whole concept, ”says Kutate ladze, who believes that the type of phage, the prescribed doses and the application method in the test were not adequate for the infection in the patients.
“It is very difficult to follow the standard classical way of approval. It is not a chemical formula ”, he adds.
Phages must match the bacteria they infect to obtain more effective results , he says.
Medical preparations also need to be updated periodically, 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 state, especially since they are natural,” says Alain Dublanchat, one of the leading proponents of phage therapy in France, which 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 phage s 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 opines.
He adds that the concentration of phages used in the Phagoburn study was also lowered to be on the safer side of drug manufacturing guidelines, a fact mentioned in several case studies on the shortcomings of the assay.
Compassionate use of phages
Despite Phagoburn’s setback, the role of phages in saving the lives of the American citizen Tom Patterson and British Cystic Fibrosis Patient Isabelle Carnell-Holdaway of Deadly Superbugs was widely publicized.
In both cases, l The phages were specially prepared and administered under compassionate use, a clause that allows the use of experimental medicine as a last resort.
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 authorized 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 according to a doctor’s prescription.
“In Belgium, we spent many years arguing with regulators, but this was a mistake,” says Jean Paul-Pirnay, Research Director of the Hospital Military Queen Astrid (QAMH) in Brussels.
“The regulators liked phage therapy, but they did not have the power or the mandate to change or replace the regulations. It was only when the minister of public health officially asked them to help us that the ball began to roll ”, he details.
Pirnay is the author of a document that describes the recommendations for the Framework of Belgium Magisterial Phage Medicine, including a regulatory system to create a seed bank of tested and certified phages needed for custom preparations.
He says there are plans underway to export this solution to the Pharmacopoeia European or pan-European regulatory solution governing the use of phages, but covid – 19 has slowed 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 a scientific article and half a science fiction plot that portrays a bleak future” characterized by human overpopulation, major alterations to 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. At present, some 700, 000 people die every year due to RAM infections.
Pirnay said the futuristic allegory was inserted in his article to highlight the urgent need for a solution.
Although 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 channel much-needed funding towards more clinical research and testing of phage for therapeutic use.
Aside from 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 phage over time , a problem that Phage researchers and clinicians have so far managed to circumvent.
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 process of coevolution in which both microbes have been part for millennia.
New research has identified the defensive immunity called he 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 aroused the interest of the pharmaceutical giants since these methods can be patented , unlike natural phages currently used for therapeutic use.
Last year, Johnson & Johnson signed an initial agreement of $ 20 Millions of dollars 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 modern research In an unprecedented study on phages, the Eliava Institute’s solid and serious work is slowly being overlooked, but its contribution to the current global discussion on phages cannot be denied, says Pirnay, who jokingly refers to the fact that its team includes two Georgian microbiologists and he 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 to share patient case studies on the internet.
Kutateladze hopes this can help others focus their research on more crucial issues.
“In my opinion, there should be much more collaboration, ”he says. “Much time and money has been spent on details that we have already researched and documented.”
The institute is currently collaborating with the Swiss group Ferring Pharmaceuticals and the American 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 treatments with phages.
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 GMP standards, a challenging task for the institute, to often cash-strapped, but which Kutateladze hopes will at some point help facilitate exports of its medical phage preparations to other countries.
This would be the ideal solution for patients like Díaz. 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 of modern medicine” , he opines.
You can read this article in its version original in English.
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