Scientists at the Baylor College of Medicine and collaborators say they have been exploring a better way of delivering medications that does not require injections but could be as easy as swallowing a pill. Their study “A bioengineered probiotic for the oral delivery of a peptide Kv1.3 channel blocker to treat rheumatoid arthritis” appears in PNAS.
“People don’t like to have injections for the rest of their lives,” said co-corresponding author Christine Beeton, PhD, professor of integrative physiology at Baylor. “In the current work, we explored the possibility of using the probiotic bacteria Lactobacillus reuteri as a novel oral drug delivery platform to treat rheumatoid arthritis in an animal model.”
Previous work from the Beeton lab had shown that a peptide derived from sea anemone toxin effectively and safely reduces disease severity in rat models of rheumatoid arthritis and patients with plaque psoriasis. “However, peptide treatment requires repeated injections, reducing patient compliance, and direct oral delivery of the peptide has low efficacy,” noted Beeton.
She began working with Robert A. Britton, PhD, professor of molecular virology and microbiology and member of the Dan L Duncan Comprehensive Cancer Center at Baylor. The Britton lab has genetically modified probiotic bacteria to produce and release compounds. In the current study, the team bioengineered the probiotic L. reuteri to secrete peptide ShK-235 derived from sea anemone toxin.
The bacteria are indigenous to human and other animal guts
They chose L. reuteri because these bacteria are indigenous to human and other animal guts. It is one of the lactic acid bacteria groups that has long been used as a cell factory in the food industry and is recognized as safe by the FDA L. reuteri has an excellent safety profile in infants, children, adults and even in an immunosuppressed population, according to Beeton.
“Engineered microbes for the delivery of biologics are a promising avenue for the treatment of various conditions such as chronic inflammatory disorders and metabolic disease. In this study, we developed a genetically engineered probiotic delivery system that delivers a peptide to the intestinal tract with high efficacy,” write the investigators.
“We constructed an inducible system in the probiotic Lactobacillus reuteri to secrete the Kv1.3 potassium blocker ShK-235 (LrS235). We show that LrS235 culture supernatants block Kv1.3 currents and preferentially inhibit human T effector memory (TEM) lymphocyte proliferation in vitro. A single oral gavage of healthy rats with LrS235 resulted in sufficient functional ShK-235 in the circulation to reduce inflammation in a delayed-type hypersensitivity model of atopic dermatitis mediated by TEM cells.
“Furthermore, the daily oral gavage of LrS235 dramatically reduced clinical signs of disease and joint inflammation in rats with a model of rheumatoid arthritis without eliciting immunogenicity against ShK-235.
“This work demonstrates the efficacy of using the probiotic L. reuteri as a novel oral delivery platform for the peptide ShK-235 and provides an efficacious strategy to deliver other biologics with great translational potential.”
“The results are encouraging,” Beeton said. “Daily delivery of these peptide-secreting bacteria, called LrS235, dramatically reduced clinical signs of disease, including joint inflammation, cartilage destruction and bone damage in an animal model of rheumatoid arthritis.”
The researchers followed bacteria LrS235 and the peptide ShK-235 it secretes inside the animal model. They found that after feeding rats live LrS235 that release ShK-235, they could detect ShK-235 into the blood circulation.
“Another reason we chose L. reuteri is that these bacteria do not remain in the gut permanently. They are removed as the gut regularly renews its inner surface layer to which the bacteria attach,” explained Beeton. “This opens the possibility for regulating treatment administration.”
More research is needed to bring this novel drug delivery system into the clinic, but the researchers anticipate that it could make treatment easier for patients in the future.
“These bacteria could be stored in capsules that can be kept on the kitchen counter,” pointed out Beeton. “A patient could take the capsules when on vacation without the need of refrigeration or carrying needles and continue treatment without the inconvenience of daily injections.”
The findings provide an alternative delivery strategy for peptide-based drugs and suggest that such techniques and principles can be applied to a broader range of drugs and the treatment of chronic inflammatory diseases.