In the good old days eating mud pies and sucking on worms in the garden was considered a normal part of growing up. Maybe not worthy of a Michelin star, and maybe some would be worried about “germs”, but who knew back then that we would eventually be actively exploring how to re-invent bacteria to help treat diseases, particularly those associated with malfunctions of the microbiome: the collective genes of the community of microorganisms our bodies play happy host to.
Re-engineering bacteria to create beneficial therapeutics was brought to my attention by a Nature article that briefly and succinctly described research, from three US-based companies, that explored a role for genetically modified bacteria in the fight against disease.
This article piqued my interest but I was left wanting more details regarding the development landscape of these modified living medicines….. and here’s what I found!
Investigations into Synlogic, Osel and Intrexon (the companies referred to in the article) revealed that since 2017, Synlogic has been collaborating with Ginkgo Bioworks to develop a discovery engine for living drugs to treat liver and neurological disorders in particular. The collaboration leverages Ginkgo’s expertise in automated high through-put organism screening and design, and Synlogic’s experience in developing re-engineered, naturally-occurring micro-organisms that contain genetic circuits that can be programmed to exist symbiotically within us and also to respond to pathophysiological signals to control the disease.
A year earlier Synlogic initiated a collaboration with Abbvie to discover and subsequently develop agents for the treatment of inflammatory bowel disease (IBD), particularly Crohn’s and ulcerative colitis.  By June 2017 the companies had announced the discovery of leads for the indications of interest.
Synlogic has two products each engineered from Escherichia coli Nissel strain under clinical investigation:
- SYNB 1020 is being investigated in hyperammonaemia and inborn urea cycle disorders; the agent received fast track designation for the former in July 2017 and is currently under phase I/II investigation for this indication in the US.
- A first-in-human trial was initiated in the US in April 2018 for SYNB 1618 in volunteers and in patients with phenylketonuria. It was given Orphan drug status in October 2017 and fast-track designation in April 2018.
Collectively, the Nature article plus several earlier published accounts have suggested that US-based Osel was intending to seek FDA approval for its re-engineered Lactobacillus jensii strain, a product to prevent vaginal HIV transmission, after it’s progresion into clinical investigation.    However, according to AdisInsight, there have been no recent reports identified for the clinical development of MucoCept in the US for this indication; indeed Osel’s product pipeline indicates that phase I investigation is yet to commence.
Further along the pipeline however, Osel has LACTIN-V, a vaginally administered modified strain of human Lactobacillus crispatus that is currently under phase II investigation for three indications related to woman’s health (prevention of bacterial vaginosis and urinary tract infections, and as an aid to in vitro fertilization). 
As a licensee, Osel is also developing a strain of Clostridium butyricum (M588; Cdactin-O), originally developed by Miyarisan Pharmaceutical Company (as Miya-BM®), and available in Japan for more than 30 years for the treatment of C. difficile-associated disease (CDAD) and antibacterial-associated diarrhoea (AAD). Osel has the rights to commercialise the agent in North America and Europe for the treatment of C. difficile infections.
The thought of bacteria being used to address an internal imbalance leading to a disease state is fascinating…and even more so when you consider the concept of multiple-therapeutics resulting from a single bacteria strain. This is essentially what Intrexon’s ActoBiotics® are. Genetic modification of Lactococcus lactis, one of the few bacteria given GRAS designation (generally recognized as safe) by the FDA, enables a variety of protein-based therapeutics to be delivered within the gastrointestinal tract via a single capsule. The engineered microbes within the capsule are said to act as “biofactories” within the gut to produce the desired therapeutics in situ.
Intrexon and Janssen Pharmaceuticals have been collaborating since 2015 to develop treatment and prevention therapeutics against type-2 diabetes mellitus, obesity and/or metabolic disorders related to energy dysregulation. In a separate collaboration with Synthetic Biologics, Intrexon is developing SYN 200, for the treatment of phenylketonuria.
Intrexon also has its own investigational programme that is developing a range of ActoBiotics® aimed at treating or preventing diabetes mellitus (type 1 and 2), phenylketonuria and digestive system disorders. Research is taking place in both the US and Europe. Investigation relating to C. difficile infections has been discontinued and there appears to be no recent reports related to the preclinical development in Coeliac disease or IBD.
… and the rest
In addition to the details discovered relating to just these three companies and their current activities within this exciting area of living drugs, a search of the AdisInsight database revealed the following:
There are close to 100 agents that are, or have been, under commercial investigation related to the human microbiome, not all are re-engineered bacterial products.
The top organisations involved in bacterial modification include Seres Therapeutics, Synlogic, Johnson & Johnson and Second Genome, some of which are via collaboration. A number of academic institutions are also associated with collaborative research programmes, most notably the Mayo Clinic.
The majority of investigation is still in the research and preclinical phase, as may be expected for this novel area of interest; the US is the most common location for investigation.
Inflammation, gastrointestinal disorders, infections and metabolic disorders are the most commonly investigated areas; not surprising given the close inter-relationships that exist between these physiological systems and general gut health.
As the Nature article highlighted, there are some concerns regarding the overall safety of ingesting bacteria that have the capabilities of transferring their genetic modifications to other pre-existing bacteria in the microbiome. However, as it also points out, research includes attempts at engineering safety aspects such as modification of the chromosomes rather than the bacterial plasmids, and including built-in processes to preclude survival of these microbes outside the body.
There is no doubt that the interest in creating living organisms modified to work with, instead of against our internal microbiotia, is blooming. Working together, science and technology will enable the discovery of the different and vital roles these miniscule organisms play, and how best to administer them to effect maximal health benefits.
Image credit: Jelleke Vanooteghem – Unsplash