Re-engineering Bacteria to Treat Diabetes

Sensing and processing by skin bacteria (Staphylococcus epidermidis) could be re-engineered to help diabetic sufferers keep their blood sugar levels in check.

A few years ago, I wrote an essay for the Biochemical Society introducing students to synthetic biology. This field applies engineering principles to design biological circuits that can do useful things. In medicine, this could mean re-engineering live bacteria to sense the amount of a particular substance in the body. The same bacteria could process and use this information to dispense medicines precisely where in the body they are needed.

As someone who makes things, I always found the thought of the Minimal Cell inspiring. The idea here is to create an organism with the smallest possible genome as a chassis on which to add other functions. Tiny live robots. The bacterium Mycoplasma genitalium was used as a starting point for the minimising, since it already has the smallest genome of any known free-living organism. The genome was made entirely of synthetic DNA - molecules that had themselves been made from scratch in a lab.

Most of the work on the Minimal Cell was done by scientists at the J. Craig Venter Institute in the United States, and I took this opportunity to see what developments they have made in the field of therapeutics. Professor John Glass has an idea to re-engineer bacteria normally resident in our skin - Staphylococcus epidermidis - for the treatment of type 1 diabetes [1].

Type 1 diabetes is a disease in which the patient’s immune system decides to destroy the pancreatic β-cells because it doesn’t like the look of them. These are the cells that make the hormone insulin in response to rising blood sugar levels after eating. If the body is unable to make insulin, it’s unable to bring down those high sugar levels. Without insulin, cells aren’t instructed to onboard sugar and without sugar, they won’t be able to produce enough energy. In desperation, they break down fats to stoke their fires - and this activity is life-threatening. High levels of the sticky sugar in the blood can also damage the parts of the body that rely on tiny threads of blood vessels - the eyes, the kidneys and the feet.

All of this means that patients with type 1 diabetes have to monitor their blood sugar levels very carefully, figure out how much insulin their body needs, and administer it themselves using a needle.

If only there was another way.

Prof. Glass’ idea is an elegant one: re-engineered skin bacteria would compute the amount of sugar in the patient’s blood and with this information, administer the right amount of insulin to get the patient’s blood sugar back under control.

This might all sound like sci-fi, but other researchers are already having success re-engineering gut bacteria to treat disease. A group led by Dr Amir Zarrinpar at UC San Diego has isolated a strain of E. coli from the gut of a mouse and re-engineered it to make bile salt hydrolase (BSH), an enzyme that breaks down bile salts. The team added the new bacteria to the gut of the mouse and monitored what happened to its sugar and insulin levels after eating.

Healthy mice treated with these re-engineered bacteria had lower blood sugar levels, and lower insulin levels, leading to the conclusion that these mice were better able to manage their blood sugar. In a mouse model of type 2 diabetes - this is the disease in which insulin is made in the pancreas, but the patient’s body is no longer able to sense it, or is unable to respond appropriately - in this model, significant improvements were seen in the mouse’s ability to sense and respond to insulin.

But could this really be a treatment some day?

Well perhaps. There are ‘live bacterial therapeutics’ (LBT) for a number of human diseases currently in clinical trials.

Precigen ActoBio recently announced successful Phase 1b and Phase 2a clinical trials with their LBT for treatment of patients recently diagnosed with type 1 diabetes. AG019 contains the bacterium Lactococcus lactis, which has been re-engineered to make two proteins, an insulin precursor molecule and possible target for the immune system in its destruction of pancreatic β-cells, and an anti-inflammatory molecule called IL-10, included to subdue the immune system.

In the clinical trials, AG019 was tested alone and also in combination with teplizumab, an antibody medication targeting a molecule called CD3. Crucially, teplizumab was used in this study because it is the first approved therapy that delays the progression of type 1 diabetes from stage 2 to stage 3 - when β-cells are still present, it helps to stop them from being attacked.

AG019 was safe and tolerated by the patients in the trials, and was found to be as effective alone as in combination with teplizumab. The treatment actually changed the make-up of the patients’ immune cell populations, making them less targeted to the pancreatic β-cells, their attention focussed elsewhere.

Unfortunately, this is where AG019’s story ends. Precigen moved to shutdown ActoBio operations this Summer, choosing instead to focus on PRGN-2012 AdenoVerse® gene therapy for the treatment of recurrent respiratory papillomatosis [2].

References

1. J. C. V. I. staff (2020) Synthetic Cell-Powered Lotion to Manage Type 1 Diabetes. J. Craig Venter Institute. Accessed November 18, 2024.

2. Precigen, Inc. (2024) Precigen Strategically Prioritizes Portfolio to Focus on First Potential Gene Therapy Launch. Precigen, Inc. Accessed November 19, 2024.

Further Reading

Charbonneau, M. R., Isabella, V. M., Li, N. et al. (2020) Developing a new class of engineered live bacterial therapeutics to treat human diseases Nat. Commun. 11:1738.

Mathieu, C., Wiedeman, A., Cerosaletti, K. et al. (2024) A first-in-human, open-label Phase 1b and a randomised, double-blind Phase 2a clinical trial in recent-onset type 1 diabetes with AG019 as monotherapy and in combination with teplizumab Diabetologia 67:27-41.

Russell, B. J. et al. (2022) Intestinal transgene delivery with native E. coli chassis allows persistent physiological changes Cell 185(17):3263-3277.e15.

Resources

Biochemical Society (2020) Minimalist Biology. Biochemical Society. Accessed November 19, 2024. A hands-on activity inspired by the idea of the Minimal Cell which I helped to develop.

Pickering, T. (2018) Diabetes: Year One Manchester: Self. A collection of graphic poems by illustrator Tony Pickering about the first year following his diagnosis with type 1 diabetes.