Selection of Disease Targets for Phage Therapy

Abstract

At present, there are many controversies surrounding the outcomes of clinical work with bacteriophage therapeutics. While phase one trials are, as expected, indicative of safety – at least for the administered dose – the limited number of phase two trials to date have been less supportive of efficacy, with only one trial providing evidence for this. This has led to a perception of failure which now risks damaging the sector as a whole. In early work in the 1920s and 1930s, use of impure preparations combined with a profound lack of understanding of the nature of bacteriophages themselves limited the probability of successful outcomes. These factors no longer apply, but it is clear that success is by no means assured. Why is this? A key issue in achieving successful results is the selection of the target indication. The many factors that need to be considered when selecting this include the nature of the infection, of the bacterial target, and of the bacteriophages themselves.

Glossary

Additive

Where the combined effect of two agents is the sum of their individual effects.

Adaptive immune system

The immune response that develops when the body recognizes a novel infective agent, including antibodies and cell-mediated immunity.

Amplification

Multiplication of a bacteriophage through multiple cycles of infection of the host bacterium.

Antagonistic

Where the combined effect of two agents is less than the sum of their individual effects.

Biofilm

A structured community of bacteria living within a complex extracellular matrix that can protect them from environmental damage and external agents.

Biological control

Use of biological or biologically sourced agents to control an infection or infestation.

Broth culture

Growth of bacteria in liquid nutrient media.

Burst size

The number of new bacteriophages released from a lytic infection of a bacterial cell.

Clinical trial

The process by which a novel drug or therapeutic is proved safe and effective for human use, ranging from phase 1 (“first in man,” safety only in healthy individuals) through phase 2 (early efficacy in affected patients) to phase 3 (large scale, premarket, in affected individuals). Other stages may exist such as the combined phase 1/2 trial that is an initial trial that evaluates both safety and efficacy.

Cocktail

A mixture of bacteriophages used for therapeutic purposes.

Declaration of Helsinki

Declaration by the World Medical Assembly covering the principles to be used for medical research involving humans. Among many other things, it lays out the principles permitting the use of experimental drugs in severely ill patients (see also “expanded access,” for which this provides the widely cited European equivalent).

EMA

The European Medicines Agency, which regulates the testing and approval of new medicines.

Encapsulation

Enclosure of a drug in a material intended to protect it and to mediate its release under specific conditions.

Endpoint

A defined outcome of a clinical trial that determines success or failure.

Environmental samples

Materials from the environment (including sewage, soil, or hospital sources) used for the isolation of novel bacteriophages.

Expanded access

A US system for providing access to experimental drugs for severely ill patients (see also “Declaration of Helsinki”).

FDA

The US Food and Drug Administration, which regulates the testing and approval of new medicines in the USA.

GMP (or cGMP)

A strictly controlled set of procedures for the manufacture of pharmaceuticals, biologicals, and a range of other products, requiring extensive documentation and intensive quality control.

Gram negative

A bacterium with a thick and complex cell wall which is not penetrated by Gram’s stain.

Immunomodulatory

Affecting the immune response.

Innate immune system

Elements of the immune system which are nonspecific and are already present on first encounter with a novel agent, including barriers, specific cell types (including NK cells and phagocytes), and a range of chemical effectors including cytokines.

Integrase

An enzyme that ingrates a viral DNA with the cellular genome.

In vitro

Literally “in glass,” in a laboratory experimental system, which may include living cells.

In vivo

Literally “in life,” in a living organism.

Lysogeny

Latency of a bacteriophage genome within the host cell, whether integrated into the host genome or maintained as an extracellular element.

Lytic

An infection which takes over and kills the host cell by lysing it.

Model systems

Either in vitro or in vivo (animal) systems used for preclinical testing.

Myriad judgement

A judgement by the US Supreme Court in 2012 (and subsequent interpretations) that limits the patentability of natural products.

Obligately lytic

A bacteriophage infection which cannot enter a lysogenic state, and can only replicate in and kill the host cell by lysing it.

Oral bioavailability

Availability of a drug when given by mouth (orally).

Otitis

Infection of the ear.

Personalized

For a bacteriophage therapeutic, construction of a therapeutic targeted at the bacterial strains present in an individual patient.

Phagocytosis

The engulfing of particles (including viruses and bacteria) by specialized cells.

Plaques

Clear zones formed on a bacterial layer in culture by the lytic action of bacteriophages.

Point of care diagnostics

Tests intended for use close to the patient.

Pseudomonas aeruginosa

The gram-negative bacterium that causes a range of infections of humans and animals, known for its high level of resistance to antibiotics.

Synergistic

Where the combined effect of two agents is greater than the sum of their individual effects.

Temperate

Of a bacteriophage, capable of entering a lysogenic state.

Topical

At the surface of the body.