The Phage Adviser

A phage therapeutic is a biological control agent, targeting bacteria, containing one or more specific bacteriophages. Thus, it is not a conventional, chemical antibiotic, and needs to be used differently. But equally, each bacteriophage component of that therapeutic is not a living organism. A seed is not a tree, and an egg is not a chicken. But, unlike viruses, they can achieve that without outside help. They have the potential to become more, but they are not yet there. Viruses can’t. They cannot achieve their full life cycle without a specific, living host. To quote myself: “A virus is a subcellular organism with a parasitic intracellular life cycle. It requires the replication machinery of a cell to replicate. It has no metabolic activity outside the host cell. Rather, it has the potential for life, in the same way that a disk containing the code for a computer program is only a potential program until it is put into the host computer. Viruses are not (as is often proposed) the simplest form of life, since their life cycle involves not only their own metabolism, but also that of the cell whose replicative machinery they use.” The basic idea is that a virus is only a complete living organism when it is inside its host cell. This is referred to as the virocell concept, and is key to understanding what a virus actually is, and what it does. See: Forterre P (2012). The Virocell Concept in “The Encyclopedia of Life Sciences”, John Wiley and Sons, Chichester; on line: https://lnkd.in/e5Q7DBcm Harper DR (2012). Viruses: Biology, Applications, Control. Garland Science, New York. https://lnkd.in/et5pUDDB   #bacteriophage #phage #virus #living #alive #parasite #virocell drh@thephageadviser.com

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𝗚𝗼𝗼𝗱 𝗠𝗮𝗻𝘂𝗳𝗮𝗰𝘁𝘂𝗿𝗶𝗻𝗴 𝗣𝗿𝗮𝗰𝘁𝗶𝗰𝗲𝘀 (𝗚𝗠𝗣) 𝗳𝗼𝗿 𝗣𝗵𝗮𝗴𝗲 𝗧𝗵𝗲𝗿𝗮𝗽𝘆: 𝗘𝗻𝘀𝘂𝗿𝗶𝗻𝗴 𝗦𝗮𝗳𝗲 𝗮𝗻𝗱 𝗘𝗳𝗳𝗲𝗰𝘁𝗶𝘃𝗲 𝗧𝗿𝗲𝗮𝘁𝗺𝗲𝗻𝘁𝘀 The European Medicines Agency defines a medicinal product as a substance intended to treat, prevent, or diagnose disease by modifying physiological functions through pharmacological, immunological, or metabolic action. Phages fit this definition well, offering a powerful tool for various applications, including: • 𝗕𝗶𝗼𝗰𝗼𝗻𝘁𝗿𝗼𝗹 𝗶𝗻 𝗮𝗴𝗿𝗶𝗰𝘂𝗹𝘁𝘂𝗿𝗲 𝗮𝗻𝗱 𝗳𝗼𝗼𝗱 𝗶𝗻𝗱𝘂𝘀𝘁𝗿𝗶𝗲𝘀, targeting harmful bacteria. • 𝗠𝗼𝗱𝘂𝗹𝗮𝘁𝗶𝗻𝗴 𝗱𝘆𝘀𝗯𝗶𝗼𝘁𝗶𝗰 𝗳𝗹𝗼𝗿𝗮 to promote health. • 𝗘𝗿𝗮𝗱𝗶𝗰𝗮𝘁𝗶𝗻𝗴 𝗽𝗮𝘁𝗵𝗼𝗴𝗲𝗻𝗶𝗰 𝗯𝗮𝗰𝘁𝗲𝗿𝗶𝗮 in humans and animals, especially against drug-resistant infections. Phages can be applied as medicinal products in two main contexts: 1. Patient-specific preparations for individual treatment, especially as a last resort under Article 37 of the Declaration of Helsinki. 2. Widely available treatments accessible over the counter, though they may not target patient-specific strains. In Belgium, for instance, the magistral preparation pathway allows phages to be legally prepared for specific patients under a medical doctor's and pharmacist’s supervision. This personalized approach makes phages available as a last-line treatment option for severe cases. To qualify as medicinal products, phages must comply with Good Manufacturing Practice (GMP) standards, ensuring that manufactured drugs are safe, effective, and consistently high-quality. GMP mandates strict oversight, from personnel training to facility and equipment qualification and raw material control, culminating in rigorous clinical trials. Africa and other low- and middle-income countries (LMICs) stand to benefit immensely from adopting such frameworks. The increasing spread of antibiotic-resistant infections—termed the “silent pandemic”—threatens global health, but LMICs face unique challenges. Limited resources, high disease burdens, and insufficient antibiotic regulation make these regions especially vulnerable. Adopting phage-based therapies can: • Enhance treatment options in cases where antibiotics fail. • Reduce dependence on antibiotics, alleviating pressure on existing antibiotic stocks. • Foster local research and production capabilities, which can stimulate economic growth and public health innovation. By investing in phage research, supportive policies, and GMP-compliant frameworks, LMICs have an opportunity to establish themselves as leaders in combating antibiotic resistance. Read more on Good Manufacturing Practices for Phage Therapy Medicinal Products in the full paper here: 👉 https://lnkd.in/dTpwXCNz Post done by: Alice Auko Owiti

Comparison between Phages and Antibiotics

When phages are given by any of the complex routes – injection, oral dosing, even aerosolization – there are two questions. Did the phages get there? Did they work when they did? And the second question is the big one, which still needs to be answered in clinical trials. Yes, there is a lot of historical evidence, as well as more recent data from individual patients. But the clinical trial data to actually, scientifically prove phages work as antibacterials is still preliminary, even now. So… why ask two questions, when the answer to one of them is key to the whole approach? Why not select indications where the efficacy of phages can be demonstrated directly? Where the answer to the question of whether the phage reached its bacterial target is simply “yes, it did”? It is notable that of the successes to date, many have been in such indications. Topical infections, where there is no need to get the phage to a diffifult to access location. Diabetic foot and leg ulcers, ear infections. Where the infected site is directly accessible. Where phages can be dropped directly onto the bacteria doing the damage. Where there is no question about whether they get to their target, because you can see them get there… That just leaves the question of whether they actually work. With no complicating factors. Which would seem to be the most sensible way to answer that one, key question? See: Fish R et al (2018). Resolving Digital Staphylococcal Osteomyelitis Using Bacteriophage-A Case Report. Antibiotics (Basel); 7: 87. Technophage, 2022. https://lnkd.in/e2AhuT4a Wright A et al (2009). A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic-resistant Pseudomonas aeruginosa; a preliminary report of efficacy. Clin Otolaryngol.; 34: 349-357. #bacteriophage #phage #delivery #topical drh@thephageadviser.com

Did you know that today, October 22nd, is World Phage Day? This day also marks the beginning of World Phage Week (October 22nd-28th), dedicated to raising awareness about the life-saving potential of #bacteriophages. These naturally occurring viruses specifically target and destroy harmful bacteria, making them a powerful tool in fighting infections. Despite their potency against bacteria, #phages are safe for humans, animals, and the environment and are among the most abundant organisms on Earth. At INCATE, we are proud to support six incredible phage-focused ventures, with even more in the pipeline. We are proud to continue supporting these groundbreaking therapies, as we strongly believe in their potential to transform healthcare. Congratulations to Kinzbio, Fagoterapia LAB S.r.l., OSPT Ltd, Invitris, PHIOGEN, and PhageOne. Keep up the amazing work! #WorldPhageDay #WorldPhageWeek #PhageTherapy 

Our phage research is now published: Targeting Pseudomonas aeruginosa biofilm with evolutionary trained bacteriophage - an innovative approach for potential phage treatment of implant infections.

So giving phages via the blood is difficult. Oral dosing has its challenges. How else can you get them into the body? What about the lung? Delivering phages through the airways? There are multiple bacterial infections of the lung which can be targeted. In particular there are those affecting patients with cystic fibrosis where bacterial infection of the lungs is a major problem. Pseudomonas aeruginosa infections are a particular concern, Delivering by a nebuliser, generating an aerosol of the drug, is often used for lung delivery, and has been used for viral agents delivering gene therapy. Could that work for phages? Yes, it could. Phages can be optimized to survive the aerosolization process, allowing delivery to the deep lung. There are challenges, especially in cystic fibrosis, where the lung becomes clogged with mucus, but it is possible to deliver phages. Even though bacteria within the lung can be targeted directly via the airways, some groups have targeted them with phages delivered via the blood, which has had some success in individual cases. But this adds extra challenges to effective treatment. And even aerosolization might not be required? Given that the airways can be heavily colonized by the target bacteria, it could be possible to deliver phages to the upper airways, relying on phages multiplying within the airways to achieve delivery to the deep lung. So why are there no phage drugs on the market yet? Well, they are coming, and clinical trials are advancing. But, as always, it takes time. See: Aslam S et al (2024). Pseudomonas aeruginosa ventricular assist device infections: findings from ineffective phage therapies in five cases. Antimicrob Agents Chemother.  68: e0172823. BioMX (2023). https://lnkd.in/dq_gd9FW Golshahi L et al (2011). In vitro lung delivery of bacteriophages KS4-M and ΦKZ using dry powder inhalers for treatment of Burkholderia cepacia complex and Pseudomonas aeruginosa infections in cystic fibrosis. J Appl Microbiol.; 110: 106-117. Ling KM, Stick SM, Kicic A (2023). Pulmonary bacteriophage and cystic fibrosis airway mucus: friends or foes? Front Med (Lausanne); 10: 1088494. Nick JA et al (2022). Host and pathogen response to bacteriophage engineered against Mycobacterium abscessus lung infection. Cell; 185: 1860-1874.e12. Rappo U (2023). Nebulized Phage Therapy for Patients with Cystic Fibrosis with Chronic Pseudomonas aeruginosa Pulmonary Infection: A Phase 1b/2a Randomized, Double-Blind, Placebo-Controlled, Multicenter Study. Open Forum Infect Dis.; 10(Suppl 2): ofad500.2474. #bacteriophage #phage #delivery #lung #cystic_fibrosis #CF #inhaled #aerosolised drh@thephageadviser.com

So what happens when phages survive passing through the stomach and make it into the gut? Then they have to find their bacterial prey. But the gut is protected and lubricated by complex layers of mucus, a thin liquid containing salts, complex glycoproteins, and elements of the immune system. Given this protection, motility (the ability to swim) may be important for gut bacteria to avoid simply being swept through the gut and eliminated. But phages can’t swim - though they may be able to grab on to the mucus on the way past. Work reported in 2004 by Chibani-Chennoufi using mice infected with E.coli showed that bacteria freshly introduced to the gut may be far more accessible to phages than bacteria which are naturally resident there. To quote, “orally applied phage remained restricted to the gut lumen… E. coli strains recently introduced into the intestines of conventional mice… were efficiently lysed in vivo by phage added to the drinking water… In contrast, the normal E. coli gut flora of conventional mice was only minimally affected by oral phage application despite the fact that in vitro the majority of the murine intestinal E. coli colonies were susceptible to the given phage cocktail.” They concluded that “the resident E. coli gut flora is physically or physiologically protected against phage infection.” Mucus. While some bacteria infections causing disease may be more accessible, at least some bacteria were shown to exist in protected niches within the gut. Think of it as a road, with pedestrians safely on the sidewalk and cars flowing past them in the roadway – on their way to the junkyard. The separation of the two protects the pedestrians unless, like freshly added bacteria in the gut, they go jaywalking… So getting phages in there may not be enough. See: Chibani-Chennoufi S et al (2004). In vitro and in vivo bacteriolytic activities of Escherichia coli phages: implications for phage therapy. Antimicrob Agents Chemother.; 48: 2558-2569. Hansson GC (2012). Role of mucus layers in gut infection and inflammation. Curr Opin Microbiol.; 15: 57-62. Kirsch JM et al (2021). Bacteriophage-Bacteria Interactions in the Gut: From Invertebrates to Mammals. Annu Rev Virol.; 8: 95-113.   #bacteriophage #phage #delivery #gut #intestine #mucus drh@thephageadviser.com

Giving phages by injection into the blood is challenging. What about using the frequently used (for conventional antibiotics) route of oral dosing? Giving phages by mouth? That has its own challenges, The gut has evolved to digest things, and it is very good at it. Phages that have been digested are not going to work very well. And, in yet another example of the body not being optimised to accept our attempts to help, to the gut a phage therapeutic looks like very thin soup. Stomach fluid contains high levels of hydrochloric acid as well as a suite of digestive enzymes ready and waiting to digest the proteins and other components in our food. And to the digestive system the proteins that form the outer part of phages look very much like food. So, to get phages through the stomach intact, they need to be protected against digestion by the harsh conditions that they encounter in the stomach. This can be achieved by neutralising the acid environment (which can result in the production of an unfortunate amount of gas) or by encapsulating the phages inside a suitable protective shell to resist the digestion, but which can release them once they have passed through the stomach into the far milder conditions of the small intestine. Many formulations have been evaluated for such encapsulation and promising results have been obtained. So, we can get phages through the stomach. But that is not the end of the story… See: Harper DR (2021). Selection of disease targets for phage therapy In D.R.Harper, S.T.Abedon, B.H. Burrowes, M.L.McConville eds. (2021). Bacteriophages: Biology, Technology, Therapy (2 volumes). Springer Nature, Vienna. ISBN 978-3319419855 #bacteriophage #phage #delivery #stomach #digestion #encapsulation drh@thephageadviser.com