Optimising pharmacokinetics of a drug is a vital stage of the development process. Pharmacokinetics relates to a drug's journey through the body, and includes drug absorption, distribution, metabolism, and excretion.
When a patient takes a drug, its concentration in the bloodstream peaks, but then diminishes over time as it is metabolised. Although it may seem attractive to increase initial doses such that they last longer in the body and reach their target site, such dosages can be met with toxicity issues.
On the other hand, frequent dosage regimes that help sustain blood concentrations are inconvenient at the best of times. So, what if there was a way of enabling long-term, non-invasive delivery of therapeutics, while ensuring optimum targeting?
Enter the synthetic probiotic bacteria: ingestible bacteria that can continuously produce a drug at a preferred rate, optimising pharmacokinetics, and defeating toxicity issues.
Background
Earlier this year, while investigating potential therapies for Multiple Sclerosis (MS), researchers from Brigham and Women’s Harvard Medical School engineered synthetic probiotic bacteria that periodically secrete lactate into the gut. The bugs performed well in mouse models, with treated mice displaying reduced MS pathology in the brain1.
MS is an autoimmune disease whereby the immune system attacks and degrades tissue of the central nervous system (CNS). Like many autoimmune diseases, treatment of MS is challenging, particularly due to the difficulty in developing drugs to penetrate the blood brain barrier (BBB) and reach the damaged tissue.
Due to this difficulty, researchers have been exploring alternative therapeutic pathways and targets. At Harvard, their attention to dendritic cells; a type of immune cell that are particularly abundant throughout the gut and the CNS. Dendritic cells help run the mechanism of “self-tolerance” by teaching the immune system what is self and what is not. Autoimmunity develops when this mechanism of self-tolerance malfunctions and the immune system starts to attack self-tissue.
A metabolic solution?
Harvard researchers discovered the existence of a regulatory negative feedback loop in dendritic cells that helps control self-tolerance, and disruption of this loop may lead to autoimmunity.
They revealed that the metabolite lactate, which is produced by activated immune cells, influences the expression of various transcription factors involved in regulating dendritic cell function via this loop1. Low lactate leads to overactivation of dendritic cells in MS, whilst a healthy immune system can sustain levels of lactate needed for feedback regulation. Interestingly, however, a synthetic increase in lactate concentration has the same effect, and this can help reduce autoreactivity.
So, how does this relate to synthetic bacteria?
Synthetic probiotic bacteria engineered to periodically secrete lactate into the gut help maintain steady lactate levels accessible to dendritic cells and control autoreactivity. When tested in mouse models of MS, the treated mice amazingly demonstrated reduced MS pathology in the brain. No bacteria were detected outside of the gut in the bloodstream, suggesting that the effect was purely a result of the biochemical signalling between the immune cells in the gut and the brain.
Is it safe?
While not a new concept, the regulation around synthetic probiotic bacteria is challenging to navigate. These bacteria are “genetically modified organisms”, and so must comply with strict regulations. Although this therapy is likely safe for human use since the strain of bacteria used has already been tested in people, the challenge with GMOs is more closely tied to their engineering and ensuring that expression of exogenous DNA is successful with no off-site modifications2. This needs to be comprehensively understood if we are to move forward with regulations.
What’s next?
The team at Harvard is investigating the potential to apply this therapy to treat other autoimmune diseases that affect other parts of the body. The outlook is that harnessing the power of living cells together with synthetic biology could provide us with the toolkit to make more personalised and targeted therapeutics.
Resources
- Sanmarco, L.M., Rone, J.M., Polonio, C.M. et al. Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells. Nature 620, 881–889 (2023). https://doi.org/10.1038/s41586-023-06409-6
- Mugwanda, K., Hamese, S., Van Zyl, W. F., Prinsloo, E., Du Plessis, M., Dicks, L. M. T., Thimiri Govinda Raj, D. B. Recent advances in genetic tools for engineering probiotic lactic acid bacteria. Biosci Rep 31 January 2023; 43 (1): BSR20211299. doi: https://doi.org/10.1042/BSR20211299
