A UCC-based researcher has come up with a promising new treatmentfor inflammatory bowel disease based on the use of modified bacteria, writes Dick Ahlstrom
A bacterium normally used by the food industry has found a new role in the treatment of debilitating human illnesses. After genetic modification the organism might provide a powerful treatment for inflammatory bowel disorders such as Crohn's Disease.
Human trials for the treatment are already under way at the Academic Medical Centre in Amsterdam. Earlier success in animal tests suggested "we have reasons to be hopeful", says Prof Lothar Steidler of University College Cork who pioneered the treatment.
"It is a new pharmacological concept which can be compared to the development of the hypodermic syringe," says Steidler, a lead researcher in the Alimentary Pharmabiotic Centre and the BioSciences Institute at UCC. "The approach depends on the use of probiotic strains of bacteria from the gut. We are trying to use them as delivery vehicles for medication."
The work focuses on Lactococcus lactis, a bacterium used by the food industry, for example in the manufacture of cheddar. It is a well understood, safe, food grade organism with no known pathology, making it ideal as a delivery system for drugs, says Steidler.
Funding for Steidler's potential new Crohn's treatment comes via Science Foundation Ireland's investigator grant programme. He moved across from Ghent University to work with Prof Fergus Shanahan at the Alimentary Pharmabiotic Centre.
The story actually began in Ghent where Steidler worked in a specialist immunology lab that produced and characterised key immune system signalling proteins known as cytokines. "The original task was producing cytokines and developing ways to produce them," he says. "We came across Lactococcus lactis and decided to try and see what it could do."
The researchers engineered the organism, inserting an extra protein-producing gene, and it proved superb at being able to deliver high quality proteins. Steidler then had a "eureka moment" when he realised that if engineered with the right cytokine the organism might provide a safe and effective treatment for inflammatory bowel disease (IBD).
At about that time in the late 1990s, patients with Crohn's Disease were receiving treatments involving the cytokine interlukin-10 (Il-10). "Il-10 dampens down the inflammatory reaction," he explains.
"We knew it [the bacterium] was completely harmless, but on the other hand we knew it would make bioactive proteins," says Steidler. He decided to insert a cloned Il-10 gene into the organism, in the process knocking out the thyA gene, the thymidine-producing gene. Thymidine is an essential component of DNA construction and without it the bacterium simply self-destructs.
"We established a system which would ensure us the strain was not viable outside the human or test animal," he says. This was essential given the widespread and "legitimate concerns" about any release of a modified organism, he adds.
They tested the engineered bacteria in a strain of mice that naturally has IBD. "We found we could cure the disease in these animals, it was quite striking," he says. "Next we wanted to try this in humans."
The bacteria make an ideal delivery system for this disease. They survive the human stomach if encapsulated and pass through to the gut where they begin to produce inflammation-reducing Il-10 right where it is needed.
They quickly run out of thymadine however and begin to die off, ensuring they can't survive and escape into the environment. "Everything we are giving is in complete containment," says Steidler. There are no natural repositories for thymidine in the environment so the organism can't survive outside.
Twelve patients are now receiving the modified organism as part of an early phase I trial. They receive freeze-dried formations of Lactococcus lactis in capsule form daily as the bacteria only remain viable for a short time in the gut where they deliver the Il-10.
"We are only at the trial stage and I don't want to give people the impression that the cure has been found," Steidler adds, but the trial is running well.
He is already trying to improve the treatment, this time using a Lactobacillus strain discovered by UCC researchers. Even before modification it produces substances that help Crohn's patients and Steidler believes that if it also carried the Il-10 gene an even better treatment might arise.
