Natural phages have been used in phage therapy since 1919, shortly after their discovery, when they were used by Félix d'Hérelle to treat children with dysentery. The rise of antibiotic resistance and low rate of discovery of new antibiotics lead to a renewed interest in phages as antibacterial agents.
Phage therapies are specific to certain bacterial strains or species and have less off-target effects on commensal microbes compared with antibiotics. However the specificity of phages means that cocktails with combinations of various phages might be necessary for clinical infections, and regulatory approval for such therapeutic cocktails can be a challenge.
The first multicentric, randomised, single blind and controlled clinical trial for phage therapy performed in accordance with Good Manufacturing Practices (GMP) and Good Clinical Practices (GCP) took pace in Europe in 2013-2017, called Phagoburn. Phagoburn was evaluated for treatment of burn wound infections. No adverse effects were observed from the phage cocktail. Efficacy needs to be improved as the phage treatment decreased bacteria in burn wounds at a slower pace than standard of care.
Potential drawbacks to phage therapy are that when phage cause lysis of bacteria, cell wall components can cause adverse immune responses in humans, bacterial biofilms may block phages from infecting the bacteria and bacteria can evolve resistance to phage infection. Researchers are attempting to overcome some of these limitations through genetic engineering of phages.
Techniques for engineering phages include Homologous Recombination, Bacteriophage Recombineering of Electroporated DNA (BRED), In Vivo Recombineering, CRISPR-Cas-Mediated Genome Engineering, rebuilding phage genomes in vitro and synthetic biology approaches such as whole-genome synthesis from synthetic oligonucleotides.
Companies developing phage therapies
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- CRISPR/Cas ToolsClustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR associated (Cas) proteins perform adaptive immune functions in prokaryotic organisms defending against foreign nucleic acids such as viruses. CRISPR/Cas tools have been adapted for use in genome editing and other DNA and RNA targeting applications.