Bugs as drugs?

Lactococcus lactis: Potential
beyond cheesemaking? 

More microbiological nostalgia, this time prompted by an article in Nature concerning another decades-old concept, the therapeutic use of genetically engineered bacteria.

The early 90s saw a spate of clinical studies involving bacteria (Clostridium and Salmonella species) capable of growing and multiplying within the oxygen-poor environment found within solid tumours, their natural anti-cancer properties enhanced through engineered expression of enzymes capable of activating cancer drugs. Response rate were far from compelling, although interest remains in their use as oncolytic “vaccines".

Listeria monocytogenes is under evaluation as a live vector for the delivery of tumour-specific antigens across a variety of cancer indications, but the treatment-related death of a cervical cancer patient (and subsequent clinical hold) in a Phase I/II combination study involving Advaxis’s L.monocytogenes HPV vaccine has raised questions as to whether the vector or AstraZeneca’s immune checkpoint, Imfinzi® (durvalumab) is the culprit.

More recent efforts are directed towards conditions other than cancer and are exploiting advances made in synthetic biology. A US company, Synlogic, is applying “therapeutic programming” to repurpose commensal bacteria by stitching in DNA encoding for environmental sensors and metabolic switches. Clinical studies have recently commenced with an E.coli strain engineered to break down phenylalanine, an amino acid that accumulates to harmful effect in those with the hereditary condition phenylketonuria, and with another engineered strain capable of breaking down ammonia in those with life-threatening blood levels arising from genetic disease or through liver failure.

Intrexon (through a subsidiary, ActoBio Therapeutics and various collaborators) is looking to repurpose the cheese makers’ friend, Lactobacillus lactis. A clinical study is underway with a strain that produces trefoil factor I, a human protein involved in the maintenance and repair of mucosal epithelium, in subjects with oral mucositis, a painful inflammation of the lining of the mouth and a common side effect of radio- and chemotherapy.

Another strain in the clinic produces an antibody fragment against tumour necrosis factor, the target of several established and effective therapies for inflammatory bowel disease and a study is planned with a strain which produces a form of insulin thought to trigger the autoimmune destruction of insulin-secreting cells in Type 1 diabetes, along with a tolerance-inducing cytokine.

While the genetic manipulation of well-characterised bacteria is relatively straightforward, the design and development of effective therapeutic strains is not without problems. Mutation and the loss of inserted plasmids can result in reversion of engineered bacteria to their wild state. Predicting the potency of modified bacteria and the likelihood of successful colonisation remains complex and uncertain. As demonstrated by antibiotic resistance, bacteria are notoriously promiscuous when it comes to sharing DNA and there is a risk that the ability to express therapeutic proteins might be passed to other bacterial species. The gut and oral microbiomes play subtle and important roles in human health and might be detrimentally altered through colonisation by engineered strains.

While none of these challenges are insurmountable, and with admiration at the ingenuity exercised in designing and developing bacterial therapeutics, I suspect that the same treatment objectives can be more readily achieved by established, less problematic, technologies, although the convergence of synthetic biology and growing understanding of the human microbiome opens some intriguing, if not near-horizon, possibilities for short or long term beneficial manipulation.

Photo credit: Kenneth Toda, University of Wisconsin

Update added 15th August 2018

Preclinical data from both mouse and primate models of phenylketonuria indicated that Synlogics's E.coli candidate,  SYNB1618, engineered to express phenylalanine-degrading enzymes can substantially lower blood phenylalanine levels. A Phase I/II clinical study is currently recruiting healthy volunteers, with results anticipated mid-2019. 

Development of a synthetic live bacterial therapeuticfor the human metabolic disease phenylketonuria. Isabella, VM et al. Nature Biotechnlology published online 13 August 2018; doi:10.1038/nbt.4222.

Genetically modified bacteria enlisted in fight against disease. Reardon, S. Nature News, online 21^st June 2018. http://tinyurl.com/y86n2mly