Proposed implementation
Sounds great on paper but what can it be used for… Check out below how we plan to bring PHANGEL into the “real world”!
The main goal for our project is to help people dealing with sepsis caused by Lipopolysaccharides (LPS) from gram-negative bacteria lysis. The approach displays its full power if used against infections caused by a multiresistant bacteria. The affected persons are usually old or have compromised immune systems1.
A septic shock is the distribution of an infection into the blood and throughout the body. So first, the immune system is unable to keep the infection local. Second, the immune system reacts in such a strong way that the body is damaged. Our approach intends to lower the second strong reaction. In case of gram-negative infections, the overreaction of the immune system is caused mostly by LPS2. The phage expresses Human Plasma Gelsolin in the target bacterium which should bind to LPS after the bacteria is killed by the phage. After talking to experts, we decided that PHANGEL needs to be given intravenously and as an addition to state of the art treatment of septic shock. However, this addition could avoid long term physical damage. A big problem treating septic shocks is the pressure of time. Since it is impossible to know which organism caused the sepsis, quick diagnosis is crucial. Our product should be given additionally to antibiotic therapy since bacteria are often unable to resist phages and antibiotics at the same time3.
One of the main safety aspects to consider is the correct downstream processing of the phages. The LPS concentration is high in the fermentation broth and the proposed application would be an intravenous injection into a weakened person. Therefore, the final formulation needs to be effectively free of endotoxins.
Proposed downstream processes for this purpose would be anion-exchange chromatography or hydrophobic interaction chromatography. It is paramount to find ways to properly purify only those phages that have been successfully modified to both contain the human gelsolin gene and lack the gene for the major capsid protein. This is to ensure that the GMO phages can truly not propagate in the patient and escape into the wild where they might influence wild phages and bacteria populations.
One of the main challenges we see with this project is the general aversion people have against GMOs, especially in Western Europe. In this regard, further work is necessary in order to convince the population that GMOs are nothing to be feared, but rather a useful tool that can benefit humanity in a variety of ways. As a result of this rather constrictive legal framework regarding GMOs, their medical application and the potential release of GMOs might make it hard to potentially get the product approved for release through the clinical trial process. However, our implemented safety measure could speed up the approval process compared to other engineered phages. Clinical trials must be designed ethically correct. Therefore, the control group needs to be treated the best known treatment for septic shocks and compared to a group receiving the same treatment plus our PHANGEL.
Another issue might be finding for profit investors to further develop this idea. The anti-GMO atmosphere might decrease the number of patients who are willing to take this medication.
For more considerations regarding the next steps of our project, read our interviews with Alexander Belcredi from PhagoMed and Dr. med. vet. Sandra Wienhold.
1Juneja, Deven. ‘Severe Sepsis and Septic Shock in the Elderly: An Overview’. World Journal of Critical Care Medicine 1, no. 1 (2012): 23. doi: 10.5492/wjccm.v1.i1.23.
2Opal, Steven M. ‘Endotoxins and Other Sepsis Triggers’. In Contributions to Nephrology, edited by C. Ronco, P. Piccinni, and M.H. Rosner, 167:14–24. Basel: KARGER, 2010. doi: 10.1159/000315915.
3Abedon, Stephen T. ‘Phage-Antibiotic Combination Treatments: Antagonistic Impacts of Antibiotics on the Pharmacodynamics of Phage Therapy?’ Antibiotics 8, no. 4 (11 October 2019): 182. doi: 10.3390/antibiotics8040182.
