“Viral Soldiers” is the title of an article about phage therapy, the use of viruses to combat bacterial infections. The great advantage of phage therapy as opposed to traditional antibiotics is the targeting of specific stains of bacteria. As has become increasingly noted, our bodies contain a plethora of bacteria that are essential for health. Antibiotics have the unfortunate side effects of killing beneficial bacteria. Additionally, due to the nature of the evolution of bacteriophages and the emerging technology of synthetic bacteriophages, they can maintain effectiveness against bacterial infections despite bacteria evolving resistance.
‘Despite the challenges still facing phage therapy, numerous companies are now looking to bring the treatments to mainstream clinics. (See table below.) In September 2015, researchers in France launched the first multicenter study and clinical trial to evaluate phage therapy. Known as Phagoburn, the project began in 2013 with preclinical work to produce two phage cocktails using methods that met European Medicines Agency (EMA) manufacturing standards. Now, the two treatments—which target burn-wound infections caused by E. coli or Pseudomonas aeruginosa—will be administered to 220 patients and the therapeutic results compared with those in patients treated with silver sulfadiazine, the current go-to drug for such infections.
Like the phage cocktails used by the Eliava Institute, the Phagoburn therapies are a mixture of naturally occurring viruses selected for their ability to target specific bacterial species. The P. aeruginosa cocktail is a mix of 13 phages, according to Patrick Jault, a Phagoburn investigator and chief of the burn treatment center at Percy Military Hospital outside of Paris; the E. coli cocktail contains 12 phages.
A handful of US companies also aim to bring phage preparations to clinical trials. In 2009, the Maryland-based firm Intralytix published the results of its Phase 1 trial for a phage therapy that targets venous leg ulcers in diabetic patients. None of the 40 or so patients who received the phage cocktail had any adverse reactions to the treatment, but the company has not said whether a Phase 2 trial is planned.13 Meanwhile, Richmond, Virginia–based AmpliPhi Biosciences announced in November it was enrolling nine patients to test the safety of a natural phage cocktail intended to treat chronic sinus infections caused by S. aureus.
These and more trials are needed to determine which phage therapies will work best for which indications, and how to scale up the production of those that are successful. “We’ve yet to see how this plays out both in the clinic and when we try to manufacture these at large scales,” says AmpliPhi CEO Scott Salka.
With these hurdles in mind, San Diego–based Synthetic Genomics, founded by synthetic biologist J. Craig Venter, is taking a different approach. Rather than mixing natural phages together, company researchers are attempting to engineer a synthetic virus that combines the properties of multiple phages into a single genome. Such engineered phages are simpler to manufacture than cocktails with dozens of different phages, says Bolyn Hubby, vice president of research and development at Synthetic Genomics. “Not having very large complex cocktails makes these products compatible with current GMP [good manufacturing process] standards.”
The company is currently applying bioinformatics and viral engineering methods to understand the natural host ranges of various phages, and then inserting genes from other viruses to expand those ranges to include other subtypes of the targeted bacterium. “By iteratively doing this, we can expand a phage’s host range while maintaining specificity so commensal bacteria are unaffected,” says Hubby. Eventually, the researchers plan to layer on additional ammunition, such as potency against biofilms or synergistic interactions with antibiotics.
In addition to phage cocktails and engineered viruses, researchers are also putting phage components to work. New York–based Contrafect and Netherlands-based Micreos, for example, use isolated lysins, the phage enzymes that rip through a bacterial envelope when a virus injects its DNA into a cell or when viral progeny burst out. Others are experimenting with just the phage tail proteins, called tailocins. (See image here.) These parts lack the ability to multiply within a host, so they avoid risks inherent to phages that carry DNA, making such protein therapies potentially much easier to manufacture and bring to market, says Rockefeller University’s Vincent Fischetti, who is a scientific advisor to Contrafect.‘
H/T Fight Aging!